Polatuzumab vedotin (DCDS4501A), a novel, targeted anti-cancer agent being developed by Genentech/Roche, is a first-in-class anti-CD79b antibody-drug conjugate or ADC currently being investigated for the treatment of several subtypes of non-Hodgkin lymphoma (NHL).
Results of a randomized phase II clinical trial, sponsored by Hoffman-LaRoche, shows that adding bendamustine and rituximab (MabThera®; Roche | Rituxan®; Genentech) to polatuzumab vedotin, significantly improved response and survival rates in a cohort of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Early results led to a U.S. Food and Drug Administration (FDA) breakthrough therapy status and EMA PRIME designation.
Laurie Helen Sehn, MD, at the BC Cancer Agency in Vancouver, Canada, noted in a presentation earlier this month during annual meeting of the American Society of Clinical Oncology (ASCO), that the improvement in overall survival in patients with relapsed/refractory diffuse large B-cell lymphoma is clearly remarkable. 
“Based on these [..] results [of the trials], polatuzumab vedotin has received breakthrough therapy designation and priority medicines designations for [the treatment of patients with] relapsed or refractory DLBCL,” Sehn noted. However, in contrast, the study results demonstrated that, in short-term follow-up, there is no clinical improvements in a cohort of follicular lymphoma (FL) patients.
The CD79b protein is highly specific and expressed in the majority of types of B-cell NHL, making it a promising target for the development of new therapies. Polatuzumab vedotin is thought to bind to CD79b, triggering internalization of the drug into the cells. This targets the cytotoxic, small-molecule chemotherapeutic payload, which is attached to the monoclonal antibody, to these B-cells. Based on an abundance caseload, this process is thought to maximize tumor cell death while, at the same time, potentially minimizing the effects on normal healthy cells. Polatuzumab vedotin is being developed by Roche utilizing Seattle Genetics proprietary antibody-drug conjugate technology.
The multicenter, open-label study of polatuzumab vedotin administered by intravenous (IV) infusion in combination with standard doses of bendamustine and rituximab or obinutuzumab in participants with relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma.
The study comprises two stages. The first stage is a Phase Ib safety run-in stage. The second stage is a Phase II stage. The anticipated time on treatment was 18 weeks for participants with diffuse large B-cell lymphoma and 24 weeks for participants with relapsed or refractory follicular lymphoma.
Sehn and colleagues included a cohort of 80 patients with diffuse large B-cell lymphoma. These patients were randomized to receive bendamustine and rituximab or polatuzumab vedotin + bendamustine and rituximab for 6 planned 21-day cycles.
The researchers also randomized another cohort of 80 patients with relapsed or refractory follicular lymphoma to receive bendamustine and rituximab or polatuzumab vedotin + bendamustine and rituximab for 6 planned 28-day cycles.
The primary endpoint was complete response (CR) assessed by fluorodeoxyglucose positron emission tomography (FDG-PET) at 6 to 8 weeks after the end of treatment.
A total of 40% of patients with diffuse large B-cell lymphoma treated with polatuzumab vedotin + bendamustine and rituximab achieved complete response at the end of treatment, versus 15% of BR-treated patients (P=0.012).
According to Sehn, the improvement of complete response translated into a significantly higher progression-free survival (PFS) (6.7 months for polatuzumab vedotin + bendamustine and rituximab vs. 2.0 months for bendamustine and rituximab, P<0.0001) and overall survival (11.8 months versus 4.7 months, P=0.0008). Furthermore, regardless of the number of prior lines of treatment for diffuse large B-cell lymphoma, and regardless of relapsed versus refractory status, FDG-PET CR rates were higher in the polatuzumab vedotin + bendamustine and rituximab arm.
By contrast, in the relapsed or refractory follicular lymphoma cohort, the FDG-PET CR rate was high for both arms, at 69% for polatuzumab vedotin + bendamustine and rituximab and 63% for bendamustine and rituximab. Shen noted that there was no significant difference in progression-free survival (P=0.58) with relatively short-term follow-up.
The most common grades 3 – 5 adverse events for both diffuse large B-cell lymphoma and patients diagnosed with follicular lymphoma were higher in the polatuzumab vedotin + bendamustine and rituximab arm than the bendamustine and rituximab arm and included cytopenias, febrile neutropenia, and infections.
Other observed serious adverse events were also higher in the polatuzumab vedotin + bendamustine and rituximab arm and included febrile neutropenia for both follicular lymphoma and diffuse large B-cell lymphoma patients and infection for patients with follicular lymphoma. Finally, a total of 5% of patients with follicular lymphoma and 18% of diffuse large B-cell lymphoma had a grade 5 event.
Commenting on the study results, Alison Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, NY noted that whether or not polatuzumab vedotin will change treatment paradigms for patients with diffuse large B-cell lymphoma may, potentially be answered by the ongoing, randomized phase III POLARIX study. This study compares polatuzumab plus R-CHP to R-CHOP in patients with previously untreated diffuse large B-cell lymphoma.
James F. Holland, MD, one of the pioneers of combination chemotherapy and cancer cooperative group research, died at the age of 92 on March 22. His wife, Jimmie C. Holland, MD, who was considered the founder of psycho-oncology, predeceased him by three months on Christmas Eve at age 89.
Jim was Distinguished Professor of Neoplastic Diseases at the Icahn School of Medicine at Mount Sinai in New York, and Jimmie was Wayne E. Chapman Chair in Psychiatric Oncology and attending psychiatrist at Memorial Sloan Kettering Cancer Center.
I knew both Jim and Jimmie, had interviewed them individually numerous times over many years, and considered them friends. They both continued to work and contribute to their fields until the end, and always had new and interesting information to share.
I first met Jimmie in 1990 when I was chairing a meeting of a group I had founded, the NCI-Designated Cancer Centers Public Affairs Network, at MSKCC and our steering committee was treated to attending grand rounds with Jimmie Holland. Several years later I was introduced to Jim.
At dinner a few years ago hosted by Stand Up To Cancer in honor of the PBS documentary series, “Ken Burns Presents Cancer: The Emperor of All Maladies,” Jimmie and I sat together and chatted most of the evening. Later on, I thanked Jim for lending me Jimmie as my girlfriend. “As long as you’re not her boyfriend,” he responded with the wit and good humor that characterized him almost as much as his outspoken manner and colorful neckties.
When I began writing a series last year for MedPage Today about pioneers in oncology, my first call for an interview was to Jimmie, who had been encouraging me for many years to write a book about the cultural or social history of cancer. She had promised to write the preface.
For the MedPage series I told her that I wanted to arrange separate interviews with her and then Jim over the next few weeks.
She replied that she thought it wise to start with Jim because of several health issues he’d been dealing with, and I took her advice.
A few months following publication of Jim’s profile, I called Jimmie again about scheduling a time to talk. She did not respond immediately and finally replied that I should contact her again in several weeks.
When we spoke, she said that she had recently undergone surgery after developing a bilateral femoral arterial emboli, and how the experience—one of the few medical issues she had encountered during her long life–had enhanced her understanding of how so many of her cancer patients had felt. She was, after all, the psychiatrist who had pioneered a field based on how people cope with a devastating disease rather than dealing with mental illness.
Our conversation, however, only lasted a short time since she was fatigued from her condition, so we rescheduled for November when she was up to speaking at length and about some things she had never discussed before.
That interview, which may have been her last, was published a month before she died in her Revolutionary-era home in Scarsdale, NY, surrounded by her family.
I wrote to Jim expressing my condolences but did not receive a reply. Then in March during an interview with Larry Norton, MD, who considered Jim a mentor and was a longtime colleague of Jimmie’s at Memorial Sloan Kettering, we discussed how Jim was following the loss of Jimmie. Larry said he had written to Jim several times but hadn’t heard back. That conversation was days before learning about Jim’s death at home from respiratory failure.
During their early years in Buffalo, N.Y., during the 1950s, Jim was chief of medicine B at Roswell Park Cancer Institute, and Jimmie was head of psychiatry at Erie County Medical Center. During an 8-year period she also had five children taking 6-month leaves between births, while pursuing her professional career.
Jimmie would relate how she had spent many evenings listening to her husband and his colleagues discuss the early development of chemotherapy and how it was making a real difference in pediatric acute lymphoblastic leukemia.
Jimmie said: “It was an exciting time in chemotherapy with new drugs coming down the pike, and I’d asked them if they asked their patients how they felt about their cancer, which helped develop my interest in issues relating to the psychological care and support of patients facing catastrophic diseases.”
She added, however, that in those days medical oncologists were not paying much attention to their patients’ quality of life since they were too engaged in the big problem of finding cures.
“They thought my concerns were just temporary stopgaps,” she said. “But I was around when we saw the first Hodgkin’s survivors. In the 1960s, we suddenly began to see people surviving.”
She said that she persuaded her husband who was a co-founder and then-head of CALGB to start a psychiatry committee that enabled the fledgling field of psychosocial oncology to add quality-of-life questions into larger protocols, providing more of a scientific basis to what was perceived as a “soft” science.
In addition to cancer-related social events I usually spent time with the Hollands at the American Association for Cancer Research (AACR) and American Society of Clinical Oncology (ASCO) annual meetings. Jim had served as president of both organizations, and every time I saw him, his inevitable reply to my, “How are you?” was always, “Still vertical, unlike many of my colleagues.”
I will sorely miss hearing that response at AACR later this month but know that Jim and Jimmie both led long, fruitful lives that had saved the lives and soothed the psyches and emotions of countless cancer patients and their loved ones.
This article part in a series of the revival of Eric Rosenthal Reports published in Onco’Zine and formerly featured in Oncology Times.
Enfortumab vedotin, being developed by scientists at Agensys (part of Astellas) in collaboration with a team of scientists at Seattle Genetics, is an investigational antibody-drug conjugate or ADC that targets Nectin-4, a cell surface protein expressed in multiple solid tumors including metastatic urothelial cancer, particularly in bladder cancer, ovarian cancer, and non-small cell lung cancer (NSCLC).
The drug is composed of a fully humanized anti-Nectin-4 antibody created by using a transgenic system, the XenoMouse®, from Amgen, and, via a proprietary linker technology developed by Seattle Genetics, attached to the synthetic cell-killing agent monomethyl auristatin E (MMAE), a microtubule-disrupting agent.
Enfortumab vedotin is the first agent to target Nectin-4, which is expressed on many solid tumors, with especially uniform expression on bladder cancers. Preclinical data demonstrate that enfortumab vedotin effectively binds to target cells, internalizes and induces cell-killing activity.
Unmet medical need
Urothelial cancer is most commonly found in the bladder (90%). According to the American Cancer Society, approximately 79,000 people in the U.S. will be diagnosed with bladder cancer during 2017 and almost 17,000 will die from the disease. Outcomes are poor for patients diagnosed with metastatic disease, with a five-year survival rate of five percent.
Based on the data from the ongoing phase I clinical trial presented today, Agensys and Seattle Genetics, who entered into an antibody-drug conjugate development collaboration in early 2007, are co-developing and eventually co-commercialize, enfortumab vedotin. As part of their collaboration the companies plan to initiate a registrational monotherapy phase II trial for locally advanced or mUC patients who have been previously treated with a therapy of checkpoint inhibitors (CPI), drugs that unleash an immune system attack on cancer cells. Furthermore, a trial evaluating enfortumab vedotin in combination with CPIs is planned for later this year as part of a broad clinical development program.
“Patients with metastatic urothelial cancer typically have a five-year survival rate of just five percent and are in urgent need of new treatment options,” explained Daniel P. Petrylak, M.D., Ph.D., Yale Cancer Center and presenter of the phase I data at ASCO.
“Despite recent clinical advances, up to 80% of patients fail to respond to checkpoint inhibitors, or CPIs, and there are no approved therapeutic options for use after CPI failure,” Petrylak addded.
“The objective response rates observed in our phase 1 analysis of enfortumab vedotin show the potential benefit of this agent for patients with metastatic urothelial cancer, particularly those who have failed checkpoint inhibitor therapy. Enfortumab vedotin was generally well-tolerated, and the most common adverse events were nausea, itching, fatigue and diarrhea,” he noted.
“Our updated enfortumab vedotin monotherapy phase I data at ASCO continue to show encouraging antitumor activity and a well-tolerated safety profile in patients with heavily pretreated metastatic urothelial cancer. We plan to initiate this year a pivotal phase II study in the CPI-pretreated setting with the intent of pursuing accelerated approval from the FDA,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.
“Enfortumab vedotin is our first late-stage clinical program for solid tumors, and these data demonstrate the potential for antibody-drug conjugates to provide therapeutic benefit across a wide array of cancers,” Drachman added.
“We are encouraged by the data we’ve seen so far in the enfortumab vedotin clinical trials,” noted Steven Benner, M.D., Senior Vice President and Global Therapeutic Area Head, Oncology Development, Astellas.
“We’re pleased to be moving forward the enfortumab vedotin development program in support of patients who may benefit from this new potential treatment option,” he further noted.
The updated results from the ongoing phase I study evaluating enfortumab vedotin as a monotherapy for mUC were presented earlier today by Daniel P. Petrylak.
The ongoing trial evaluated the safety and anti-tumor activity of enfortumab vedotin at escalating doses of 0.5 to 1.25 milligrams per kilogram (mg/kg) weekly for three of every four week cycles. The data presented included a total of 81 patients diagnosed with mUC with a median age of 67 years.
Thirty seven patients (46%) were previously treated with checkpoint inhibitors and 77 (95%) had undergone treatment with a platinum-based chemotherapy. Ninety-seven percent of patient screening samples showed Nectin-4 expression, the majority of which were at a high level. All response rates include confirmed and unconfirmed responses, as assessed by the investigator. The recommended phase II dose (RP2D) has been established at 1.25 mg/kg.
The results of the study show that of the 71 patients evaluated for response, 29 patients (41%) had an objective response, including three (4%) complete responses and 26 (37%) partial responses. Disease control was achieved in 51 patients (72%), defined as the sum of patients achieving complete responses, partial responses or stable disease.
The preliminary estimate of median duration of response for all patients was 24 weeks.
In 30 patients treated at the RP2D level, 16 patients (53%) had an objective response, including one (3%) complete response and 15 (50%) partial responses. Disease control was achieved for 22 patients (73%).
Of the 32 patients previously treated with checkpoint inhibitors and evaluated for response, 14 patients (44%) had an objective response, including one complete response (3%) and 13 (41%) partial responses. At the RP2D, eight out of 17 CPI-treated patients (47%) achieved a partial response, and disease control occurred in 13 patients (77%).
Of the 19 patients with liver metastases, nine (47%) had an objective response, including one (5% five perc) complete response and eight (42 percent) partial responses. Disease control was achieved for 13 patients (68%).
The most common treatment-related adverse events of any grade occurring in 10 percent or more of patients were nausea (36%), pruritus (31%, fatigue (30%) and diarrhea (28%). The most common Grade 3 or 4 adverse events occurring in five percent or more of patients, regardless of attribution, were urinary tract infections, hypophosphatemia, hyponatremia and anemia.
Overall, the trial results support further development of enfortumab vedotin as monotherapy and in combination with other therapies for patients with mUC. Enrollment is ongoing at the RP2D in patients with mUC who have been previously treated with checkpoint inhibitors.
Data from a trials in progress abstract presented during the 2017 annual meeting of the American Society of Clinical Oncology (ASCO) confirmed the continued advancement of Mersana Therapeutics Phase I clinical trial of XMT-1522.
Mersana is a clinical-stage biotechnology company focused on discovering and developing a pipeline of antibody-drug conjugates or ADCs based on the company’s proprietary Dolaflexin® platform with DolaLock payload technology.
XMT-1522 is an antibody-drug conjugate or ADC consisting of a novel human IgG1 anti-HER2 monoclonal antibody conjugated to a proprietary auristatin-based cytotoxic payload.
An average of 12 auristatin-based cytotoxic payload molecules are, via a biodegradable polymer, conjugated to each antibody .
In October, 2016, U.S. Food and Drug Administration (FDA) cleared Mersana’s Investigational New Drug (IND) application to begin Phase I clinical trials for XMT-1522, which is the company’s first pipeline product, and could define a new class of HER2-targeted therapies.
The Phase Ib trial is an open label, multi-center study of XMT-1522 administered as an intravenous infusion once every three weeks.
The dose escalation part of the study is designed to help establish the maximum tolerated dose or recommended Phase II dose for in patients with advanced breast cancer and either a HER2 immunohistochemistry (IHC) score of at least 1+ using a validated IHC assay or with evidence of HER2 amplification.
Patients with HER2 positive (by IHC or amplification) gastric cancer or nonsmall cell lung cancer may also be eligible for participation in the dose escalation part of the trial. Upon completion of dose escalation, the cohort expansion segment of the study is designed to consist of four parallel cohorts of different patients groups to confirm the maximum tolerated dose or the recommended Phase II dose and estimate the objective response in each of the patient populations.
“The clinical experience with XMT-1522 to date has been consistent with the promising preclinical data,” noted Donald A. Bergstrom, M.D., Ph.D., Chief Medical Officer, Mersana Therapeutics.
“We look forward to providing interim Phase I results for XMT-1522 at a scientific conference later in 2017 as well as beginning clinical trials in Q1 2018 with XMT-1536, our second Dolaflexin ADC.”
“We anticipate that the Phase I data for these two assets will establish the potential of the Dolaflexin ADC platform to generate products that bring meaningful clinical benefit to patients,” Bergstrom cocluded.
This year the premier oncology event – the annual meeting of the American Society of Clinical Oncology (ASCO), is just around the corner. The 53rd annual ASCO meeting will be held from June 2 to June 6 at the McCormick Place in Chicago, Ill.
Historically, the goal of ASCO was to foster communication among oncology-related subspecialties, as well as the exchange of a wide range of ideas related to cancer. This year expect even more coverage and exchange of ideas designed to benefit cancer patients. This year expect more information about targeted, personalized medicine, including antibody-drug conjugates, PD-1s and small-molecule drug conjugates as well as companion imaging agents for focused, personalized, diagnostics.
DS-8201 and U3-1402
Daiichi Sankyo will present research new data on its lead antibody-drug conjugates DS-8201 and U3-1402. In particular, clinical results from a phase I study of DS-8201 will be discussed during a Clinical Science Symposium on June 5 at 9:45 a.m. CT. DS-8201 and U3-1402 use Daiichi Sankyo’s proprietary linker-payload technology.
DS-8201 is an investigational ADC in phase I clinical development for HER2-positive advanced or metastatic breast cancer or gastric cancer, HER2-low-expressing breast cancer and other HER2-expressing solid cancers. The U.S. Food and Drug Administration (FDA) granted Fast Track designation to DS-8201 for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including ado-trastuzumab emtansine (T-DM1).
U3-1402 is an investigational and potential first-in-class ADC currently in phase I clinical development for HER3-positive metastatic or unresectable breast cancer.
Overexpression of epidermal growth factor receptors (EGFR), such as HER2 and HER3, can play a role in cancer cell development, including breast cancer.  Statistics show that one in five breast cancers overexpress HER2, which is associated with more aggressive disease. Additionally, studies show that approximately 50 to 70% of breast cancer tumors have detectable levels of HER3.  Patients living with invasive breast cancer with high levels of HER3 may face a significantly worse prognosis and decreased survival.
Depending on several factors, including the biomarker classification (HR+, HER2+ or triple negative), breast cancer is typically treated with various combinations of surgery, radiation, chemotherapy, hormone therapy or targeted therapy.  But many HER2-positive tumors progress to the point where no currently approved HER2-targeting treatments can continue to control the disease.  Furthermore, there is no HER2-targeting therapies approved for HER2-weak positive tumors (IHC2+/ISH negative or IHC+) and no approved HER3-targeting therapy options. Hence, a better understanding of HER3 regulation should improve the strategies to therapeutically target HER3 for cancer therapy.
Promising safety and efficacy data from monotherapy and combination studies with mirvetuximab soravtansine in patients with folate receptor alpha (FRα)-positive epithelial ovarian cancer (EOC) will be presented during the 2017 ASCO meeting.
These data include results from pooled analyses of three Phase I expansion cohorts and from a Phase Ib/II study, FORWARD II, evaluating mirvetuximab soravtansine in combination with Avastin® (bevacizumab), carboplatin, Doxil® (pegylated liposomal doxorubicin), or Keytruda® (pembrolizumab).
Data from the pooled analyses demonstrate the safety and efficacy profile of mirvetuximab soravtansine in the patient population eligible for the ongoing Phase III registration trial, FORWARD I. These data include 113 EOC patients treated with mirvetuximab soravtansine in three expansion cohorts in the Phase 1 trial. In the subset of 36 patients meeting the key eligibility criteria for FORWARD I, which includes patients with platinum-resistant disease and medium or high levels of FRα and who have received up to three prior lines of therapy, the confirmed overall response rate (ORR) was 47% (95% CI 30, 65) and median progression-free survival (mPFS) was 6.7 months (95% CI 4.1, 8.3).
“The data observed with mirvetuximab compare favorably with outcomes typically achieved with currently available single-agent therapies for platinum resistant ovarian cancer. Current single-agent therapies for platinum-resistant ovarian cancer have low response rates of 15 to 20% and short median progression-free survival of three to four months,” noted Kathleen Moore, M.D., Associate Professor, Department of Obstetrics and Gynecology at the Stephenson Cancer Center at the University of Oklahoma.
“Based on the consistent safety and efficacy seen with mirvetuximab soravtansine reflected in these pooled analyses, particularly in those patients meeting the eligibility criteria for the pivotal study, I am very encouraged about the potential of this compound in patients with platinum-resistant ovarian cancer and look forward to continued progress with the ongoing Phase III FORWARD I trial,” Moore added.
For all 113 patients, the median number of prior regimens was 3, 85% had platinum-resistant disease, 67% had prior bevacizumab, and 22% had a prior poly (ADP-ribose) polymerase (PARP) inhibitor. The safety profile of the pooled population was consistent with data previously reported during the 2016 ASCO Annual Meeting, which consisted primarily of low grade, manageable adverse events. In this heavily pretreated group of patients, the confirmed ORR was 30% (95% CI 22, 39) and mPFS was 4.3 months (95% CI 3.9, 5.4).
Small molecule drug conjugates
Scientists at Endocyte will present two posters on the company’s lead, clinical-stage agents, EC1456 and EC1169.
The updated data on EC1456-01 comes from a two part phase I dose escalation (Part A) and expansion (Part B) study. The presentation includes data for 87 Part A treated patients with advanced solid tumors and 6 Part B treated patients with FR-positive non-small cell lung cancer (NSCLC) as of the data cutoff on May 18, 2017. In this trial, all patients were imaged to assess folate receptor expression with 99mTc-etarfolatide (FR expression not an eligibility criteria for Part A). Preliminary data from our first patient enrolled in the EC1456 ovarian surgical study, EC1456-02, will also be presented.
An update also will be provided for EC1169-01, a two-part phase I dose escalation (Part A) and expansion (Part B) study in patients with metastatic castration-resistant prostate cancer (mCRPC). The presentation includes data for the expansion phase (Part B) for 24 taxane-exposed mCRPC patients and 16 taxane-naïve mCRPC patients as of the data cutoff on May 15, 2017. All patients were imaged to assess PSMA expression with 99mTc-EC0652 (PSMA expression not an eligibility criteria).
This year, the objectives by the ASCO meeting’s organizers are to advance the education of physicians and other healthcare professionals caring for patients with cancer, to support the development of clinical cancer researchers and novel anti-cancer medications, and to facilitate the delivery of high-quality health care to patients with cancer. To meet this goal, the 2017 annual meeting is designed to serve the respective interests all – healthcare professionals and patients – with education focused on medical, surgical, and radiation oncology.
The abstracts for the 2017 annual meeting have been released earlier this month. While we’ve discussed some of the exciting updates, we believe that there is a lot more exciting information to be release during the upcoming meeting.
Clinical data for ASG-15ME and Enfortumab vedotin, also known as ASG-22ME and ASG-22M6E, presented at the American Society of Clinical Oncology‘s (ASCO) 51st Annual Meeting held June 3-7, 2016, in Chicago, IL, shows strong clinical activity of these two novel antibody-drug conjugates (ADCs).
ASG-15ME and Enfortumab vedotin are investigational antibody-drug conjugates (ADCs) that consist of monoclonal antibodies designed to deliver microtubule-disrupting agents selectively to tumor cells. In both drugs, the linker system is designed to be stable in the bloodstream and release the cell-killing agent once inside target cancer cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.
ASG-15ME (Product name AGS15E) is a potent, investigational, Monomethyl Auristatin E (MMAE)-based antibody-drug conjugate linked via a protease-cleavable linker to the SLITRK6-specific human gamma 2 antibody (Igγ2).
SLITRK6, a proteins that are highly expressed in urothelial cancers, particularly bladder cancer, is a member of the SLITRK family of neuronal transmembrane proteins. It was discovered as tumor antigen expressed in multiple epithelial tumors, including bladder, lung, and breast cancer as well as in glioblastoma. 
The trial drug is the first and only agent to target SLITRK6, a transmembrane protein identified as an ADC target by researchers at Astellas’ subsidiary Agensys, which is expressed on many solid tumors. Preclinical data demonstrate that ASG-15ME effectively binds to target cells, internalizes and induces cell-killing activity
Nectin-4 Enfortumab vedotin targets Nectin-4, which can be found on multiple solid tumors, including bladder, breast, lung and pancreatic. Nectin-4, which is a valuable serum marker for breast carcinoma, is involved in calcium ions (Ca2+) and play a vital role in the physiology and biochemistry of organisms and the cell.
As a 66-kDa type I transmembrane glycoprotein, Nectin-4, part of the class of embryonic carcino-antigens and belonging to the Nectin family of calcium-independent immunoglobulin (Ig)-superfamily proteins, it is both a homophilic and heterophilic cell adhesion molecule (CAMs).
The Nectin family comprises of a total of five transmembrane glycoproteins (PVR/CD155, Nectin-1/CD111, Nectin-2/CD112, Nectin-3, and Nectin-4), which are all members of the immunoglobulin superfamily.
A soluble form of Nectin-4 (43 kDa) is generated from the membrane protein via the action of the tumor necrosis factor-alpha converting enzyme TACE/ADAM-17, which plays a fundamental role in diverse processes including angiogenesis and cancer through their activities in cell adhesion/fusion, membrane protein shedding, and signal transduction.
As an investigational drug, enfortumab vedotin is composed of an anti-Nectin-4 monoclonal antibody attached, via an enzyme-cleavable linker, to the microtubule-disrupting agent MMAE. The trial drug, which uses Seattle Genetics’ proprietary linker technology, is currently in a phase I clinical trial to evaluate the safety and antitumor activity of escalating doses of ASG-22ME in patients with solid tumors.
Enfortumab vedotin is the first and only agent to target Nectin-4, identified as an ADC-target by Agensys’ researchers. Preclinical data demonstrate that enfortumab vedotin effectively binds to target cells, internalizes and induces cell-killing activity.
Bladder cancer begins when cells in the urinary bladder start to grow uncontrollably. Most bladder cancers start in the innermost lining of the bladder, which is called the urothelium or transitional epithelium. Urothelial carcinoma, also known as transitional cell carcinoma (TCC), is the most common type of bladder cancer. Urothelial carcinoma starts in the urothelial cells that line the inside of the bladder.
While patients with early stage bladder cancer are treated with curative intent, outcomes are poor for patients diagnosed with locally advanced or metastatic disease. For the approximately 10 percent of patients with urothelial bladder cancer whose initial diagnoses occur when they have metastatic disease, the average five-year survival is approximately 15%. According to the American Cancer Society, in 2016 approximately 77,000 people will be diagnosed and more than 16,000 will die from urothelial bladder cancer.
“Bladder cancer is the fifth most common cancer in the U.S., and there have been few treatment advances over the past three decades. For metastatic disease, the five-year survival rate is only 15 percent, representing a significant unmet need to identify additional treatment options,” noted Len Reyno, MD, senior vice president and chief medical officer, Agensys, an affiliate of Astellas.
”We are pleased to present these first data for ASG-15ME and ASG-22ME in urothelial cancers, which have a particularly high unmet medical need,” Reyno said.
“The clinical data from the phase I presented at ASCO from the ASG-15ME and enfortumab vedotin programs in heavily pretreated metastatic bladder cancer patients show a manageable safety profile along with objective response rates that are higher than historical rates seen with taxanes,” said Jonathan Drachman, MD, chief medical officer and executive vice president, Research and Development at Seattle Genetics.
“We will continue enrolling patients in the ongoing phase I clinical trials to determine the recommended dose for further development,” Drachman continued.
During the annual meeting of the American Society of Clinical Oncology data were reported from 49 patients with metastatic urothelial cancer.  The median age of patients was 64 years. Of the 49 patients, 48 patients (98%) had undergone treatment with a platinum-based chemotherapy regimen, including 33 patients (67%) with a cisplatin-based regimen, and 14 patients (29%) who had progressed on or after treatment with checkpoint inhibitors.
A total of twenty-nine patients (59%) had received two or more prior systemic therapies. The primary endpoints of the ongoing clinical trial are to evaluate escalating doses, pharmacokinetics and safety of ASG-15ME as a monotherapy. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. In this dose-escalation study, patients received ASG-15ME at 0.1 to 1.25 milligrams per kilogram (mg/kg) weekly for three of every four week cycles.
The researchers found that of the 43 patients evaluable for response, 14 patients (33%) had an objective response (OR), including one patient (2%) who achieved a complete response and 13 patients (30%) who achieved a partial response. While the study is ongoing, preliminary estimates show median duration of response at 16.1 weeks. Disease control was achieved for 27 patients (63%), defined as achieving complete remission (CR), partial remission (PR) or stable disease (SD).
In 16 patients treated at the 1.0 mg/kg dose level, seven patients (44%) had an objective response. In five patients treated at the 1.25 mg/kg dose level, two patients (40%) had an objective response. In the 13 patients whose cancer had metastasized to the liver, four patients (31%) achieved a partial remission. Bladder cancer that metastasizes to the liver typically has a poor prognosis. In the 14 patients who had previously been treated with checkpoint inhibitors, five patients (36%) achieved a partial remission.
The most common treatment-related adverse events of any grade occurring in 15% or more of patients were fatigue (43%) and nausea (20%). Peripheral neuropathy was observed in 10 patients (19%) at Grade 1 and six patients (11%) at Grade 2. No Grade 3 or 4 peripheral neuropathy was reported.
In the study, eight patients developed ocular symptoms with corneal abnormalities. The majority of patients were managed with dose reductions and recovered.
Based on the results, researchers concluded that ASG-15ME targeting SLITRK6 is well tolerated and active, warranting an ongoing study of ASG-15ME in patients with metastatic urothelial cancer. Enrollment is ongoing at 1.0 and 1.25 mg/kg to identify a recommended dose for future studies.
Data were reported from 44 patients with metastatic urothelial cancer.  The median age of patients was 66.5 years. Of the 44 patients, 43 patients (98%) had undergone treatment with a platinum-based chemotherapy regimen, including 30 patients (68%) with a cisplatin-based regimen, and 12 patients (27%) who had progressed on or after treatment with checkpoint inhibitors. Twenty-eight patients (64%) had received two or more prior systemic therapies.
The primary endpoints of the ongoing clinical trial are to evaluate escalating doses, pharmacokinetics and safety of enfortumab vedotin as a monotherapy. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. In this dose-escalation study, patients received enfortumab vedotin at 0.5 to 1.25 mg/kg weekly for three of every four week cycles.
The researchers found that of the 36 patients evaluable for response, 10 patients (28%) achieved a partial response (PR). While the study is ongoing, preliminary estimates show median duration of response at 16.1 weeks. Disease control was achieved for 25 patients (69%), defined as achieving complete remission, partial remission or stable disease.
In eight patients treated at the 1.25 mg/kg dose level, four patients (50%) had an objective response. In the 10 patients whose cancer had metastasized to the liver, four patients (40%) achieved a partial remission. Bladder cancer that metastasizes to the liver typically has a poor prognosis. In the 12 patients who had previously been treated with checkpoint inhibitors, three patients (25%) achieved a partial remission.
The most common treatment-related adverse events of any grade occurring in 15 percent or more of patients were pruritis and nausea (30% each), fatigue (25%), diarrhea (21%) and rash (18%). Peripheral neuropathy was observed in 11 patients (19%) at Grade 1 and three patients (5%) at Grade 2. No Grade 3 or 4 peripheral neuropathy was reported. In this study, two patients developed ocular symptoms with corneal abnormalities. The patients were managed with dose reductions and/or steroid eye drops.
These results warrant ongoing study of ASG-22ME. Hence, enrollment is ongoing at 1.0 and 1.25 mg/kg to identify a recommended dose for future studies.
The ASG-15ME and enfortumab vedotin phase I clinical trials are ongoing to identify a recommended dose for future clinical evaluation.
Agensys (subsequently acquired by Astellas) and Seattle Genetics, the companies developing ASG-15ME and Enfortumab vedotin, entered into the ADC collaboration in January 2007 and expanded it in November 2009.
Under the collaboration and following regulatory approval, the companies are co-developing and plan to globally co-commercialize the two investigational drugs.
Last Editorial Review: June 7, 2016 Last update: June 10, 2016
Chemotherapy remains the standard of care in the treatment of many types of cancer. However, one of the problems with chemotherapeutics is that it damages – and kills – not only cancer cells but also healthy ones.
In a pursuit to develop more targeted therapies, scientists at AbbVie and their partners at Seattle Genetics and other companies are working on novel therapies, including antibody-drug conjugates, designed to target cancer and reduce the impact of chemotherapy on healthy cells. In addition, ADCs are also expected to reduce the amount of cytotoxic, anticancer drug needed for treatment.
But what’s more, based on the company’s dual variable domain (DVD) antibody technology, scientists at AbbVie are also investigating the potential to develop ADCs that can target two proteins at once.
Scientists from Abbvie will present data from multiple clinical trials evaluating the company’s portfolio of investigational oncology medicines during the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO), June 3-7, 2016 in Chicago.
Notably, researchers will present data from studies evaluating the efficacy of ABT-414 as monotherapy in epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (GBM),  an aggressive malignant primary brain tumor. (van den Bent et al.; Abstract 2542; Poster Session; Sunday, June 5, 2016; 8-11:30 a.m. CDT)
During ASCO data data will also be presented from a phase I, open-label, dose-escalation and expansion study of ABBV-399, an investigational ADC targeting c-Met, in patients with advanced solid tumors (Strickler et al.; Abstract 2510; Poster Session; Sunday, June 5, 2016; 8-11:30 a.m. CDT with Poster Discussion Sunday, June 5, 2016; 11:30 a.m.-12:45 p.m. CDT).
Commenting on the large number of oral and poster presentations to be presented during ASCO, Michael Severino, MD, executive vice president of research and development and chief scientific officer, of AbbVie noted: “The multiple data presentations … underscore [our] commitment to pursue new cancer therapy options, with the potential to make a real and remarkable impact on the lives of people affected by cancer.”
“[We’re] committed to working together with the oncology research community, healthcare and clinical experts, industry peers, patients and patient advocacy groups, to discover and develop therapies with the goal of transforming the treatment of cancer,” Severino concluded.
Over the last years, Abbvie has demonstrated that a desire to develop medicines that make a transformational improvement in cancer treatment and outcomes for cancer patients. This drive was again emphasized in April when the company announced that it had entered into a collaboration with CytomX Therapeutics to co-develop and co-commercialize Probody™ Drug Conjugates against CD71, also known as transferrin receptor 1 (TfR1) and stated it has acquired Stemcentrx, the developer of a late-stage antibody-drug conjugate, rovalpituzumab tesirine (Rova-T; S16LD6.5) currently in registrational trials for small cell lung cancer (SCLC).
CD71, the target of CytomX’ Probody™ Drug Conjugates, is highly expressed in a number of solid and hematologic cancers and has attractive molecular properties for efficient delivery of cytotoxic payloads to tumor cells. Probody therapeutics are designed to take advantage of unique conditions in the tumor microenvironment to enhance the tumor-targeting features of an antibody and reduce drug activity in healthy tissues.
Rovalpituzumab tesirine is a novel biomarker-specific therapy that is derived from cancer stem cells and targets delta-like protein 3 (DLL3) that is expressed in more than 80% of SCLC patient tumors and is not present in healthy tissue. The investigational drug combines a targeted antibody that delivers a cytotoxic agent directly to the DLL3-expressing cancer cells while minimizing toxicity to healthy cells.
In Phase I/II studies of relapsed SCLC patients who have previously failed one or more standard therapies, rovalpituzumab tesirine demonstrated overall response rates of 44% in the patients identified with high expression of DLL3. The expression of DLL3 suggests rovalpituzumab tesirine may also be useful across multiple tumor types, including metastatic melanoma, glioblastoma multiforme, prostate, pancreatic and colorectal cancers, where DLL3 expression ranges from 50-80%.
“[Rovalpituzumab tesirine] is the first predictive biomarker-based therapy associated with drug efficacy in small cell lung cancer, ” said Charles Rudin, M.D., Ph.D., chief, thoracic oncology service, Memorial Sloan Kettering Cancer Center. “And that is a big deal for this difficult disease,” he concluded.
During the meeting of the European Cancer Congress in Vienna, Austria, in September 2015, results from a phase I trial with rovalpituzumab tesirine in 79 patients with SCLC who had progressed after first line or second line therapy were presented.
“While other cancers have multiple treatment options, there is only one agent approved in SCLC, and none available in the third line setting; the outlook for these patients is dismal,” M. Catherine Pietanza, MD, an Assistant Attending Physician at the Memorial Sloan Kettering Cancer Center, New York, noted.
Third line therapy is given after first and second line treatments have failed to halt the progression of disease.
In this trial, the patients ranged in age from 44-81, with a median age of 62 years. As is normal in phase I trials, they received escalating doses of rovalpituzumab tesirine once every three weeks until toxicity reached a point at which the increase in dose needed to be stopped.
“Of the 48 tumor samples we were able to analyse, 33 were positive for DLL3. Among the 29 DLL3+ patients we could treat at the maximum tolerated dose of rovalpituzumab tesirine, ten (34%) had a partial response and nine (31%) had disease stabilisation. The duration of response among these patients was more than 178 days, with no cases of disease progression,” Pietanza explained.
During the upcoming annual meeting of updated trial data of rovalpituzumab tesirine will be presented (Rudin et al.; Late Breaking Abstract 8505; Oral Abstract Session; Sunday, June 5, 2016; 9:44-9:56 a.m. CDT and Peng et al; Abstract 11611; Poster Session; Monday, June 6, 2016; 1:00 – 4.30).
Beyond rovalpituzumab tesirine
Beyond rovalpituzumab tesirine, Stemcentrx, now part of AbbVie, has four novel compounds in clinical trials, including antibody-drug conjugates. These novel compounds include new treatments across several solid tumor indications, including triple-negative breast cancer, ovarian cancer and non-small cell lung cancer. The company has additional pre-clinical compounds advancing toward clinical trials in 2016 and a proprietary technology platform that leverages stem cell biology to identify and screen potential targets against live tumor tissue to more predictably advance discovery and development of new assets.
By exploring and investing in new pathways, technologies and approaches, the scientists at AbbVie are breaking ground in some of the most widespread and difficult-to-treat cancers.
For a complete overview of oral and poster presentation covering antibody-drug conjugates, click here.
Only a few weeks until the start of the 2016 annual meeting of the American Society of Clinical Oncology (ASCO). This year’s ASCO, taking place in the McCormick Place convention center in Chicago, Illinois, June 3-7, is expected to attract as many as 30,000 oncology professionals from the United States and around the world.
The theme of the annual meeting is Collective Wisdom: The Future of Patient-Centered Care and Research, emphasizing that the combined knowledge from various disciplines, cancer types, treatment approaches, and big data technologies is essential to progress. The theme is noticeable throughout the entire annual meeting and reinforces the inextricable link – a necessity – between ongoing research and advances in patient-centered care. The 2016 theme is also evident as the latest, most exciting discoveries, based on a better understanding of cancer biology and chemistry, will be presented.
In preparation of the meeting, the program coordinators have accepted more than 5,200 abstracts to the ASCO Annual Meeting. Additional Late-Breaking Abstracts (LBAs), including Plenary abstracts, will be released on-site throughout the Annual Meeting.
Quality and access to care
Improving quality as well as access to appropriate care is a key subject being discussed during the 2016 annual meeting. Care may come in different forms, and researchers will discuss a phase III trial exploring whether using a mobile device-friendly web application for symptom monitoring improves survival of patients with lung cancer (Abstract LBA9006). Another study discusses a large analysis examining use of aggressive medical care and hospice for patients younger than age 65 in the last 30 days of life (Abstract LBA10033). Another study exploring racial disparities in receipt of breast and ovarian cancer risk-reducing procedures among younger breast cancer survivors with BRCA mutations (Abstract LBA1504). Cost of novel cancer therapeutics plays a role in access to these drugs. An analysis of cancer drug prices around the world (Abstract LBA6500) is expected to shine some light on the discrepancy in the availability of care.
One of the exciting development in the treatment of cancer includes immunotherapy. During the upcoming annual meeting, researchers will highlight studies representing the range of research topics, discuss survival data from early pre-clinical to phase III trials with a number of (novel) antibody-drug conjugates (ADCs) and other targeted therapies, include PD-1’s and BiTe’s.
Antibody-drug conjugates have, over the last decade, revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumor-associated target antigens and deliver a highly potent cytotoxic agent.
Today there are multiple ADCs in clinical trials, targeting varied antigens using different linker chemistries and cytotoxic payloads. In the development novel ADCs, scientists have met a number of challenges including how to improve the therapeutic index, the selection of the optimal target, a better understanding of mechanism of action (MOA), how to manage and understand off-target toxicities, as well as the selection of appropriate clinical settings where these novel drugs may have the highest clinical benefit. 
Optimal target selection
The identification of optimal target is key to the clinical advancement of new antibody-drug conjugates. The possibilities of these novel targeted drugs used in the treatment of a wide range of solid cancers and hematological malignancies is limited by the discovery of suitable targets. Optimal targets are highly expressed on cancer cells and not, or minimally, on normal, healthy, tissues.
On Sunday morning, June 5, Howard A. Burris, MD (Sarah Cannon Research Institute) will be discussing the importance of the discovery of unique targets for antibody-drug conjugates designed to “make chemotherapy great again.”
Brentuximab vedotin Brentuximab vedotin (also known as SGN-035; Adcetris® by Seattle Genetics Inc.) is an antibody-drug conjugate (ADC) or immunoconjugate directed to CD30, which is expressed in classical hodgkin lymphoma and systemic anaplastic large cell lymphoma.
This year, as part of ASCO’s oral abstract session “Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia,” on Saturday June 4, Steven I. Park, MD (University of North Carolina Lineberger Comprehensive Cancer Center) will present data from phase II trial of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by brentuximab vedotin consolidation in limited stage non-bulky Hodgkin lymphoma (Abstract 7508).
During the poster discussion session on Monday, June 6, Anas Younes, MD (Memorial Sloan Kettering Cancer Center) will discuss results from Checkmate 205, a phase II study comparing safety and efficacy of nivolumab (Opdivo®; Bristol-Myers Squibb), a programmed death-1 (or PD-1) inhibitor approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of melanoma and advanced non-small cell lung cancer, in classical Hodgkin lymphoma after autologous stem cell transplant (ASCT) and brentuximab vedotin. (Abstract 7535, Poster Board: #91).
On Monday, Philippe Armand, MD, PhD (Dana-Farber Cancer Institute) will share an update of a phase I/II study to evaluate safety and efficacy of nivolumab plus brentuximab vedotin in patients with CD30-expressing relapsed/refractory non-Hodgkin lymphomas. (Abstract TPS7576; Poster Board: #130a).
Another poster, presented by Somali C. Gavane, MBBS (Memorial Sloan Kettering Cancer Center) on Monday, includes an update of metabolic tumor volume to predict event-free survival in patients with relapsed/refractory Hodgkin lymphomas treated with brentuximab vedotin-based salvage therapy (Abstract 11566, Poster Board: #263).
Ado-trastuzumab emtansine, also know all T-DM1 (Kadcyla®; Genentech/Roche) is an antibody-drug conjugate consisting of the recombinant anti-epidermal growth factor receptor 2 (HER2) antibody trastuzumab conjugated to the maytansinoid DM1 via a nonreducible thioether linkage (MCC). The trastuzumab moiety binds to HER2 on tumor cell surface surfaces. Following internalization, the DM1 is released and binds to tubulin, thereby disrupting microtubule assembly/disassembly dynamics and inhibiting cell division and the proliferation of cancer cells that overexpress HER2.
The linkage of antibody and drug through a nonreducible linker has shown to contribute to the improved efficacy and reduced toxicity of ado-trastuzumab emtansine compared to similar ADCs constructed with reducible linkers.
During the 2016 annual meeting, results from a large number of studies with ado-trastuzumab emtansine will be presented:
On Sunday, June 5, Carlos H. Barrios (PUCRS School of Medicine) will present a poster covering patient-reported outcomes from MARIANNE: A phase III study of trastuzumab emtansine (T-DM1) +/- pertuzumab vs. trastuzumab + taxane for the treatment of HER2-positive advanced breast cancer (Abstract 593, Poster Board: #81);
The same day Audrey Mailliez, MD (Centre Oscar Lambert) will present response to ado-trastuzumab emtansine according to RANO criteria in central nervous system metastases of HER2 positive breast cancers (Abstract 605, Poster Board: #93);
Sunil S. Badve, MD (Indiana University) will present an update from the EMILIA trial discussing the role of tumor infiltrating lymphocytes (TILs) in HER2+ metastatic breast cancers (MBC) treated with ado-trastuzumab emtansine (T-DM1) or lapatinib plus capecitabine (Abstract 607, Poster Board: #95);
During the same poster session, Rachel A. Freedman, MD, MPH (Dana-Farber Cancer Institute) will present data about adjuvant ado-trastuzumab emtansine (T-DM1) for older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. (Abstract TPS629, Poster Board: #109a).
Finally, Kathy Miller, MD (Indiana University Melvin and Bren Simon Cancer Center) will present results from the HERMIONE-trial, a phase II randomized, open label trial comparing MM-302 + trastuzumab with chemotherapy of physician’s choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine. (Abstract TPS631, Poster Board: #110a)
During an oral abstract session on Monday, June 6 (breast cancer—HER2/ER), Sara A. Hurvitz (David Geffen School of Medicine, University of California Los Angeles) will discuss pathologic complete response (pCR) rates after neoadjuvant ado-trastuzumab emtansine + pertuzumab vs. docetaxel + carboplatin + trastuzumab + pertuzumab (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (KRISTINE). (Abstract 500)
The anti-Trop-2-SN-38 antibody-drug conjugate (ADC) sacituzumab govitecan (IMMU-132), being developed by Immunomedics (Morris Plains, NJ 07950), is designed to deliver the moderately-toxic conventional chemotherapeutic drug, SN-38, the active metabolite of irinotecan (Camptosar®, Pfizer), site-specifically and at a high drug to antibody ratio (DAR), to a humanized antibody that targets the Trop-2 receptor, expressed by many solid cancers, while reducing overall toxic effects that are usually found with conventional administration of these chemotherapeutic agents.
During the clinical science symposium “Future directions in breast cancer treatment: new drugs, new markers,” on Friday, June 3, Aditya Bardia, MD, MPH (Massachusetts General Hospital Cancer Center) will present results from a phase II study of sacituzumab govitecan, for the treatment relapsed/refractory metastatic triple-negative breast cancer (mTNBC) (Abstract LBA509).
Results with the first-in-class antibody-drug conjugate sacituzumab govitecan in patients with previously treated metastatic small-cell lung cancer (mSCLC) will be presented in a poster session by Alexander Starodub, MD, PhD (Indiana University Health Goshen Center for Cancer Care) on Saturday, June 4, discussing “Lung Cancer—Non-Small Cell Local-Regional, Small Cell and Other Thoracic Cancers” (Abstract 8559; Poster Board: #187)
On Monday, June 6, during the clinical science symposium “Raising the bar for targeted therapies for lung cancers,” D. Ross Camidge, MD, PhD (University of Colorado), will present new approaches to the treatment of metastatic, non-small cell lung cancer (mNSCLC) with sacituzumab govitecan (Abstract 9011).
Rovalpituzumab tesirine combines a novel targeted drug (anti-DLL3 antibody) with a toxin, D6.5 pyrrolobenzodiazepine (PBD), which is conjugated to cysteine residues on the SC16 antibody via a maleimide-containing linker with an eight-carbon polyethylene glycol spacer, cathepsin B–cleavable valine-alanine dipeptide, and self-immolating group, with a mean drug-to-antibody ratio (DAR) of 2. 
On Sunday, June 5, Charles M. Rudin, MD, PhD (Memorial Sloan Kettering Cancer Center) will present results from a phase I/II study investigating the safety and efficacy of antibody-drug conjugate rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate, for the treatment of recurrent or refractory small cell lung cancer (SCLC) (Abstract LBA8505).
New indication of rovalpituzumab tesirine also include the potential treatment of metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas (NECs). Initial results are presented in a poster presentation on June 6 by Stemcentrx‘s Stanford L. Peng, MD, PhD will present (Abstract 11611, Poster Board: #308).
Prostrate-specific membrane antigen or PSMA is a protein that is highly expressed on most of the tumor cells in prostate cancer. The protein is also expressed on the (neo)vasculature that supplies blood to many other tumors. Researchers at Ambrx (La Jolla, CA 92037) have developed a site specific antibody-drug conjugate using the company’s proprietary drug payload. The trial drug, which is being evaluating for efficacy and overall toxicity compared with conventional antibody-drug conjugates, may have the potential to demonstrate increased potency in cancer patients while decreasing the toxicity that is usually seen in other antibody-drug conjugates due to the heterogeneity of the random conjugation approach used to generate these molecules. The anti-PSMA ADC is being developed for the treatment of patients with prostate cancer and glioblastoma multiforme.
On Saturday, June 4, Heinrich Elinzano, MD (Rhode Island Hospital) will present results of the Phase II Brown University Oncology Research Group Study investigation the novel PSMA ADC in patients with progressive glioblastoma (Abstract 2065; Poster Board: #252)
The potential treatment of glioblastoma (GBM), the most common malignant primary brain tumor, is also presented by Martin J. Van Den Bent, MD (Erasmus MC Cancer Center) in a poster presentation reviewing the efficacy of ABT-414 (AbbVie), composed of the antibody ABT-806 targeting active EGFR/mutant EGFRvIII linked to the anti-microtubule agent monomethyl auristatin F, as monotherapy in epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (Abstract 2542; Poster Board: #242).
Scientists have identified aberrant EGFR expression and signaling as a hallmark of cancer growth and survival. In several EGFR-overexpressing tumor xenografts ABT-414 has shown potent anti tumor activity.
The antibody-drug conjugates enfortumab vedotin comprises the human anti-nectin-4 antibody conjugated to the highly potent microtubule disrupting agent monomethyl auristatin E (MMAE). Scientists at Agensys (Santa Monica, CA, 90404) prepared hybridoma (AGS-22M6E) and CHO (ASG-22CE) versions of enfortumab vedotin (also known as ASG-22ME). They were able to bind the the versions of enfortumab vedotin to cell surface expressed nectin-4, a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules and reported high affinity and induced cell death in vitro in a dose-dependent manner. 
Using mouse xenograft models of human breast, bladder, pancreatic, and lung cancers, scientists found that treatment with enfortumab vedotin significantly inhibited the growth these tumor types. They also noted tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors, and support further clinical development, investigation, and application of nectin-4-targeting ADCs.
On Monday, June 6, during a poster session covering genitourinary (non-prostate) cancers, Jonathan E. Rosenberg, MD (Memorial Sloan Kettering Cancer Center) will present data of the anti-tumor activity, safety and pharmacokinetics of ASG-22CE (ASG-22ME; enfortumab vedotin) in a phase I dose escalation trial in patients with metastatic urothelial cancer. (Abstract 4533, Poster Board: #156).
Inotuzumab ozogamicin is an investigational ADC comprised of a humanized IgG4 anti-CD22 antibody targeting CD22, a cell surface antigen expressed on approximately 90% of B-cell malignancies, covalently linked to N-acetyl-gamma-calicheamicin dimethyl hydrazine or calichDMH, a derivative of gamma calicheamicin, a cytotoxic antibiotic produced by the bacterium Micromonospora echinospora, with potential antineoplastic activity.
When inotuzumab ozogamicin binds to the CD22 antigen on malignant B-cells, it is rapidly internalized, delivering the conjugated CalichDMH intracellularly. The CalichDMH moiety then binds to the minor groove of DNA in a sequence-specific manner, resulting in double-strand DNA breaks and apoptosis.
The trial drug originates from a collaboration between Pfizer and Celltech (now part of UCB).
During the poster session “Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant” on Monday, June 6, a total of 3 posters with trial updates covering inotuzumab ozogamicin will be presented:
Hagop M Kantarjian, MD (The University of Texas MD Anderson Cancer Center, Department of Leukemia) will present patient-reported outcomes from a global phase III randomized controlled trial of inotuzumab ozogamicin vs. standard care for relapsed/refractory (R/R) acute lymphoblastic leukemia or ALL. (Abstract 7027, Poster Board: #19);
Daniel J. DeAngelo, MD, PhD (Dana-Farber Cancer Institute) will present the efficacy and safety by prior therapy of inotuzumab ozogamicin for the treatment of patients with relapsed/refractory acute lymphoblastic leukemia in the phase III INO-VATE trial.(Abstract 7028, Poster Board: #20), and
Elias Jabbour, MD (The University of Texas MD Anderson Cancer Center) will follow with data of the efficacy and safety of inotuzumab ozogamicin in older patients with relapsed/refractory acute lymphoblastic leukemia (ALL) who were enrolled in the phase III INO-VATE trial.(Abstract 7029,Poster Board: #21).
The presented results stem from the INO-VATE trial, is an open-label, randomized, Phase III study evaluating the safety and efficacy of inotuzumab ozogamicin as compared with a defined set of chemotherapy choices in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL).
The two primary endpoints in this trial are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Secondary endpoints include progression-free survival, volume of distribution and systemic clearance for inotuzumab ozogamicin in serum, duration of response, rate of stem-cell transplantation, minimal residual disease, cytogenetics, safety and quality of life based on the EORTC’s Quality of Life Questionnaire.
A (poster) presentation by George R. Blumenschein, M.D., Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, presents the results of a phase I study of anti-mesothelin antibody drug conjugate anetumab ravtansine, also known asBAY 94-9343, being developed by Bayer HealthCare under an agreement with ImmunoGen, consists of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a disulfide-containing linker (Abstract 2509; Poster Board: #209). 
Upon internalization, the DM4 moiety in anetumab ravtansine binds to tubulin and disrupts microtubule assembly/disassembly dynamics, resulting in inhibition of cell division and cell growth of mesothelin-expressing tumor cells. Mesothelin is overexpressed on all mesotheliomas as well as many ovarian and pancreatic cancers while minimally expressed on normal tissue. 
Results from a number of studies with antibody-drug conjugates presented during ASCO include:
Results from a phase I, open-label, dose-escalation and expansion study of ABBV-399 (AbbVie), an antibody drug conjugate targeting c-Met, in patients with advanced solid tumors. (Abstract 2510; Poster Board: #210), presented by John H. Strickler, MD (Duke University Medical Center)
A poster presentation by Carlos Alberto Gomez-Roca, MD (Institut Universitaire du Cancer de Toulouse) detailing the results of a phase I study of SAR566658, an anti CA6-antibody-drug conjugate created by ImmunoGen and licensed preclinically to Sanofi, in patients with CA6-positive advanced solid tumors (STs)(NCT01156870). SAR566658 comprises of ImmunoGen’s huDS6 CA6-targeting antibody conjugated to DM4 via one of the compansy’s engineered linkers (SPDB). (Abstract 2511; Poster Board: #211)
Results from mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate in clinical trials as single agent activity in platinum-resistant epithelial ovarian cancer patients will be presented by Kathleen N. Moore, MD (University of Oklahoma Health Sciences Center) (Abstract 5567; Poster Board: #390)
Data from a randomized, open-label, phase II study of the anti-NaPi2b antibody-drug conjugate Lifastuzumab (Lifa) Vedotin, also known as DNIB0600A and RG-7599, being developed by Genentech/Roche, compared to pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer, will be presented by Susana N. Banerjee, MBBS, MA, PhD, MRCP (Royal Marsden Hospital). (Abstract 5569; Poster Board: #392).
Nanotechnology is a multidisciplinary field opening the door to a new generation of devices for cancer diagnosis, treatment and prevention. Drug-loaded nanoparticles offer considerable potential to provide a potentially ideal solution to solve some of the problems seen with traditional chemotherapy.
Although nanoparticles can become concentrated preferentially to tumors by virtue of the enhanced permeability and retention (EPR) effect of the vasculature, the low selectivity of nanoparticles towards the cancer cells hinders the advantages of the nanoparticle formulation for efficient chemotherapy. One reason is that a therapeutic agents such as docetaxel, a commercially successful oncology drug that suffers from a poor safety profile limiting its clinical utility, also kills healthy cells. To solve this problem, scientist have been working on the development of novel drugs containing docetaxel.
CRLX301 is a novel nanoparticle-drug conjugate (NDC) containing a docetaxel payload being developed by Cerulean Pharma (Waltham, MA 02451) for the treatment of patients with refractory solid tumors. The trial drug is expected to be differentiated from standard docetaxel because it is designed to concentrate more docetaxel in tumor cells and spare healthy tissue. Preclinical data show that CRLX301 had lower toxicity than has been reported with docetaxel in preclinical studies.
Ben Markman, MBBS, FRACP (Monash Cancer Center) will presents phase I trial results of CRLX301. (Abstract 2526; Poster Board: #226).
It’s just a few more weeks until the start of the 2016 annual meeting of American Society of Clinical Oncology. To help attendees plan their meeting, ASCO has developed a a new scheduling tool – the iPlanner – to browse abstract titles, search for sessions, or create a customized schedule. In addition, the organizers have developed a new ‘Insiders Guide‘ designed to help meeting attendees navigate the ASCO and make the best of their time during the 2016 annual meeting.
Every year, in addition to offering a forum to share clinical updates in all areas of oncology, ASCO offers it’s audience a valuable opportunity to actively participate in discussions with colleagues, conforming it’s standing among the leading oncology meetings around the globe.
Last Editorial Review: May 7, 2016 Last Editorial update: May 8, 2016
Results from the German phase II ADAPT study (WSG-ADAPT), showed that neoadjuvant ado-trastuzumab emtansine (T-DM1, Kadcyla®; Genentech/Roche) is effective in the treatment of HER2-positive, hormone receptor (HR)-positive breast cancer, with or without endocrine therapy. The trial compared this therapy with the treatment of trastuzumab (Herceptin®; Genetech/Roche) and endocrine therapy.
The results of an interim analysis of the ADAPT study were presented by the researchers during the 51 Annual Meeting of the American Society of Clinical Oncology (ASCO), held May 29 – June 2, 2015 in Chicago, Illinois (ASCO, abstract 506).
The ADAPT study is one of the first new generation (neo)adjuvant clinical trials dealing with the individualization of (neo)adjuvant decision-making in the treatment of early breast cancer. The “umbrella” study, with approximately 5,000 participating patients (n = 4,936) with early primary breast cancer (BC) aged between 18 and 75 years old, aims to establish early predictive surrogate markers for therapy response under a short, 3-week, induction treatment (using the baseline diagnostic and repeat core biopsy following induction) in order to maximally individualize and optimize therapy and avoid a patient’s exposure to unnecessary toxicity as a result of ineffective or over-/undertreatment in luminal tumors. The study has now been closed because efficacy was reached. 
A subgroup of the ADAPT study included patients with various breast cancer phenotypes including HER2-positive, HR-positive early breast cancer. This substudy enrolled a total of 376 patients at 48 sites. The results of the interim analysis presented at this year’s ASCO meeting included 130 of the patients enrolled in the substudy. Participating patients with HER2+ and HR+ breast cancer were randomized to receive either (neo)adjuvant ado-trastuzumab emtansine mono therapy (N = 37), ado-trastuzumab emtansine with endocrine therapy (n = 48), or trastuzumab with endocrine therapy (n = 45) at 3.6 mg/kg. This treatment was administered in 4 cycles and followed by surgery + 1-year treatment of the standard adjuvant chemotherapy + trastuzumab.
Ado-trastuzumab emtansine, a conjugated version of the humanized anti-HER2 IgG1, trastuzumab, to a small molecule cytotoxin microtubule inhibitor DM1. Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor mediated internalization and subsequent lysosomal degradation. This results in intracellular release of DM1-containing cytotoxic catabolites. The binding of DMl to tubulin disrupts microtubule networks in the cell, which in turn causing cell cycle arrest and apoptotic cell death.
The drug is used as a single-agent for the treatment of patients with HER2-positive, metastatic breast cancer who have previously received trastuzumab and a taxane – either separately or in combination.
In the ADAPT study, researchers noted, after only 12 weeks of treatment, a clinical meaningful rate of pathologic complete response (pCR), defined as no invasive tumor in breast and lymph nodes (ypT0), of 40.5% with ado-trastuzumab emtansine alone, 45.8% with ado-trastuzumab emtansine and endocrine therapy, and only 6.7% with trastuzumab and endocrine therapy (P < 0.001 for both ado-trastuzumab emtansine groups vs. trastuzumab). Ongoing biomarker analyses included PI3K mutations and intrinsic subtypes.
The treatment results with ado-trastuzumab emtansine differed by menopausal status. The researchers noted that of the 130 patients analyzed, a significantly larger number was premenopausal (range 45.8%-60%). The majority of tumors encountered were larger than 2 centimeters (range, 45.9%-57.8%) while a third of participating patients were node positive (range, 27.1%-37.8%). About 75% of patients across all three of the arms had G3 disease.
The analysis showed that more postmenopausal women benefitted when ado-trastuzumab emtansine monotherapy was used compared with premenopausal women. They also noted that adding endocrine therapy did not noticably change the treatment outcome.
Overall, the researchers observed low overall toxicity with 16 serious adverse events in 13 patients and only 7 grade 3 adverse events related to the study medications. Interestingly, they noticed that in treatment-naive patients, some of the adverse events seen in single-agent use of ado-trastuzumab emtansine were less frequent in the combination arm.
The most common all-grade adverse events in were thrombocytopenia (30%), alanine aminotransferase increase (22%), aspartate aminotransferase increase (19%) and infections and infestations (11%). All participating patients recovered completely
The data presented during this year’s ASCO are, at this time, only an interim analysis. Experts are eagerly looking forward to the complete data analysis, which is expected to be presented during a future meeting. The complete data analysis will offer a more robust picture of the trial results of this unique study.
Last Editorial review: June 24, 2015
Photo: General Views at the American Society of Clinical Oncology (ASCO) Annual Meeting, Saturday, May 30, 2015. Over 30,000 physicians, researchers and healthcare professionals from over 100 countries are attending the 51st Annual Meeting which is being held at the McCormick Place convention center. The Annual Meeting highlights the latest findings in all major areas of oncology from basic through clinical and epidemiological studies. Photo Courtesey: ASCO/David Eulitt
With the 2015 Annual Meeting of the American Society of Clinical Oncology(ASCO), which was held in Chicago, Illinois, May 29 – June 2, now a few weeks behind us and our post-conference review of the latest data from numerous abstracts, trial updates and presentations in full swing, two clinical trial/drug development programs have caught our attention: IMGN853 (mirvetuximab soravtansine; ImmunoGen) and IMMU-132 (sacituzumab govitecan; Immunomedics).
The first trial program is that of mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting Antibody-drug Conjugate. FRα is highly expressed in many cases of epithelial ovarian cancer as well as on other types of solid tumors including endometrial cancer and some non-small cell lung cancers (adenocarcinoma), making it a good target for the potential treatment of these cancers.
The drug, being developed by ImmunoGen, is the first and only FRα-targeting ADC to enter clinical testing. It is currently being assessed for the treatment of FRα-positive, platinum-resistant ovarian cancer and for FRα-positive relapsed/refractory endometrial cancer, with additional assessments anticipated.
Mirvetuximab soravtansine comprises a FRα-binding antibody which is conjugated to a highly potent maytansinoid (DM4) that induces cell-cycle arrest and cell death by targeting microtubules. The antibody serves to target the DM4 specifically to FRα-positive cancer cells which the DM4 can then kill. 
Platinum-resistant Ovarian Cancer
Mirvetuximab soravtansine targets an important unmet need in the treatment of ovarian cancer. Each year, there are approximately 21,300 new cases of ovarian cancer diagnosed in the United States and more than 14,200 women die from the disease.  Researchers at ImmunoGen estimate that approximately 2,000-3,000 of these women have FRα-positive, platinum-resistant ovarian cancer previously treated with at least three prior lines of therapy.
The standard, first-line, therapy for ovarian cancer is a platinum-based regimen, including carboplatin (Paraplatin®; Bristol-Myers Squibb/BMS plus a taxane and potentially additional agents). Once the cancer becomes platinum-resistant, which means that the disease recurs rapidly (within six months), patients may receive non-platinum-based chemotherapies given as single-agent therapy, such as pegylated liposomal doxorubicin (Doxil®/Caelyx®; Janssen Biotech) or paclitaxel (Taxol®; Bristol-Myers Squibb/BMS). However, response rates with these agents in the second-/third-line setting are typically around 15-20%.  Unlike current treatment for platinum-sensitive patients, treatment in the platinum-resistant setting typically yields low tumor response rates. Patients also experience shorter progression-free survival (PFS) and overall survival (OS). In the advanced setting, treatment becomes largely palliative.
Clinical trial eligibility
Before considered eligible for enrollment and participation in the expansion cohort with mirvetuximab soravtansine, patients must have ovarian cancer that responded to primary platinum therapy, but has then progressed within six months or progressed on or within six months of treatment with subsequent platinum therapy. The cancer must also be FRα-positive, assessed by immunohistochemistry. Approximately 80% of patients screened met this criteria based on the CLIA lab assay.
To obtain additional experience in this patient population, the expansion cohort has been expanded from 20 to 40 patients.
Mirvetuximab Soravtansine (IMGN853): Trial Results
This year trial results were presented during the annual meeting of the American Society of Clinical Oncology (ASCO) of the first clinical findings in a disease-specific patient population with ImmunoGen’s unique, FRα-targeting ADC, mirvetuximab soravtansine (ASCO abstract #5518) 
The findings reported at this year’s are from an ongoing Phase I trial. Once the recommended Phase II dose (RP2D) of mirvetuximab soravtansine was established during dose finding (ASCO abstract #5558), an expansion cohort was opened to assess the safety and activity of this ADC specifically in the treatment of patients with FRα-positive platinum-resistant ovarian cancer. Approximately 80% of the patients screened have met the criteria for having FRα-positive disease.
Twenty-two patients were included in the analysis reported during ASCO – two from the dose-escalation phase of the trial and the twenty enrolled in the expansion cohort at the time of data cutoff for presentation (April 30, 2015). All had FRα-positive platinum-resistant ovarian cancer and had received mirvetuximab soravtansine at the RP2D (6.0 mg/kg, given every three weeks). Furthermore, all participating patients had previously received taxane as well as platinum therapy. Thirteen of these patients were still on study at the time of data cutoff.
The majority of adverse events reported were low grade (grade 1 or 2), with diarrhea, blurred vision, nausea, vomiting, fatigue, and abdominal pain the most common treatment-emergent events reported ( > 20% of patients).
Seventeen of the 22 patients were included in the efficacy analysis; the other five patients were still on study and had not yet reached their first assessment.
Other findings included:
Nine of these 17 patients had an objective response (8 partial responses, 1 complete response) to treatment, for an ORR of 53%.
The responses in six of these nine patients were ongoing at the time of data cutoff, with five of these six patients on treatment for more than 15 weeks.
“These initial clinical findings with mirvetuximab soravtansine in the treatment of patients with FRα-positive platinum-resistant ovarian cancer are highly encouraging,” noted Kathleen Moore MD, Mai Eager Anderson Chair of Cancer Clinical Trials, Stephenson Cancer Center, University of Oklahoma HSC. “There is a significant need for new therapies for patients with ovarian cancer, including platinum-resistant disease.”
Single agent treatment
“Based on these findings, we are implementing a development plan designed to advance mirvetuximab soravtansine as quickly as possible while also recognizing the potential to benefit the greatest number of patients,” commented Charles Morris, M.B., Ch.B. MRCP, Executive Vice President and Chief Development Officer at ImmunoGen. “We’re preparing to initiate a Phase II trial in late 2015 that will assess this ADC as a single-agent treatment for patients with FRα-positive platinum-resistant ovarian cancer. It is possible that this trial could be used for registration in this patient population.”
“At the same time, we’re preparing to initiate testing of mirvetuximab soravtansine in combination regimens as a potential therapy for patients with less heavily pretreated ovarian cancer. We’re also continuing to explore this promising ADC as a treatment for other types of FRα-positive solid tumors, including target-positive endometrial cancer. To complement our own research, ImmunoGen recently entered into a collaboration with the National Comprehensive Cancer Network® (NCCN) Oncology Research Program to investigate mirvetuximab soravtansine in additional preclinical and clinical studies,” Morris continued.
Sacituzumab govitecan (IMMU-132): Impressive results in SCLC
The second antibody-drug conjugate to be noted by our team was that of the investigational drug sacituzumab govitecan (IMMU-132) for the treatment of patients with relapsed/refractory metastatic non–small cell lung cancer (NSCLC) who have failed two prior lines of therapy, including targeted therapies such as an ALK inhibitor, EGFR inhibitor, and, if applicable, a PD-1 inhibitor.
The investigational drug, which was recently awarded fast track designation by the U.S. Food and rug Administration (FDA) and considered to be a next-generation antibody-drug conjugate, is also assessed in patients with relapsed small cell lung cancer (SCLC). The data presented at this year’s ASCO meeting was welcome news since SCLC, a fatal disease, has not seen new drug approvals for nearly 2 decades.
Sacituzumab govitecan targets the cell surface glycoprotein called TROP-2 on cancer cells. This glycoprotein is highly expressed in most epithelial cancers, including non-small and small cell lung cancers (NSCLC and SCLC). In contrast, there is little or no expression of TROP-2 in normal tissues. Various studies show that TROP-2 expression correlates with tumor aggressiveness. Combined with the fact that TROP-2 is selectively expressed in tumor cells, interest in TROP-2 as a potential -attractive – therapeutic target for the treatment of cancer immunotherapy has over the last decade, increased. 
Sacituzumab govitecan is an antibody-drug conjugate being developed by Immunomedics in which the antibody part of the drug binds to TROP-2. Further, the antibody part of the drug (the anti–TROP-2 humanized monoclonal antibody hRS7) is site-specifically linked to the active metabolite of the topoisomerase inhibitor, camptothecin (irinotecan), SN-38, using a proprietary linker.
In contrast to most antibody-drug conjugates in clinical development that use hyper-toxic drugs and stable linkers, sacituzumab govitecan includes a moderately toxic drug with a moderately stable carbonate bond between SN-38 and the linker.  However, in vitro and in vivo preclinical data confirms that sacituzumab govitecan is most efficacious at a high drug-antibody ratio (DAR) of 7.6 (7.6 moles SN-38/IgG). The same data shows that in a human cancer xenograft the investigational drug is capable of delivering up to 136-fold more SN-38 than its parental drug irinotecan.
A phase I study confirmed that sacituzumab govitecan has acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. 
Trial results of a yet another trial of 19 patients with SCLC treated with sacituzumab govitecan, presented at this year’s ASCO meeting were impressive: 26% of patients had partial responses, and another 27% had stabilization of disease. (ASCO abstract #2504) 
Triple Negative Breast Cancer
Sacituzumab govitecan is also associated with encouraging clinical activity and limited toxicity in patients with metastatic triple-negative breast cancer (TNBC) who have received multiple prior lines of therapy, including topoisomerase inhibitors, but were refractory or relapsing to these prior therapies. 
Patients with metastatic TNBC, which is negative for estrogen and progesterone receptors, as well as human epidermal growth factor receptor 2 (HER2), have an aggressive disease with only limited therapeutic options. This type of breast cancer comprises about 15-20% of all invasive breast cancers and is more prevalent in young and African-American women. Despite the fact that initial responses with chemotherapy are high, TNBC characteristically has a high recurrence rate and is perhaps the most difficult type of breast cancer to treat successfully with current cytotoxic agents. Media progression-free survival (PFS) in the range of 2.9 – 3.7 months has been reported in recent clinical studies in patients with metastatic TNBC following chemotherapy. Currently, there are no targeted treatments available for TNBC. Hence, there is a major unmet need for better therapies.
TROP-2 is highly expressed in most TNBC ( > 90%) and clinical trial data presented at this year’s ASCO meeting of 174 patients with relapsed/refractory diverse epithelial tumors (including 49 patients with TNBC; median age = 51 ys (range, 33-81), median of 4 prior chemotherapies) who have been treated with sacituzumab govitecan, confirm that further studies with this novel agent are, indeed, warrants.
The data included 49 patients with metastatic triple-negative breast cancer evaluated for response to treatments with sacituzumab govitecan in a mid-stage clinical study. In total, 31%, or 15 patients, showed a reduction in tumor size of 30% or more. This include 2 patients with complete response (CR). Response assessments were based on the rules set by the Response Evaluation Criteria In Solid Tumors (RECIST 1.1). Adding the 22 patients with responses between less than 30% tumor shrinkage and less than 20% tumor increase, the disease control rate was 76%.
“Given that a majority of the patients enrolled into this study had failed 4 or more prior cancer therapies, some as many as 11, we are quite encouraged with sacituzumab govitecan in this late-stage setting in an aggressive disease that is difficult to treat,” noted Aditya Bardia, MD, MPH, an Instructor at Department of Medicine, Harvard Medical School, and Assistant Physician, Medical Oncology, Massachusetts General Hospital Cancer Center in Boston, MA who presented the data.
The data presented at this year’s ASCO meeting – for both mirvetuximab soravtansine and sacituzumab govitecan – offers renewed hope for patients with difficult to treat cancers.
Last editorial review: June 23, 2015.
Photo: Annual Meeting of the American Society of Clinical Oncology (ASCO); May 29 June 2, 2015, Chicago, Illinois. Photo courtesy: Sunvalley Communication, LLC