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PEER-REVIEWED ARTICLES

Encouraging Data for Novel ADC Presented at ESMO 2016

During the annual meeting of the European Society for Medical Oncology (ESMO) being held October 7 – 11, 2016 in Copenhagen, Denmark, preliminary data for PF-06647020 in advanced solid tumors was presented as part of a Late Breaking Abstract/Poster Discussion Session (Abstract LBA35). [1]

The study was initially designed as a dose-escalation study to evaluate safety, pharmacokinetics and antitumor activity for patients with advanced solid tumors. A pre-planned expansion for ovarian cancer included 27 patients that received PF-06647020.

esmo_2016_logoClinical trial data also confirms that the use of PTK7-targeted therapy resulted in a response of approximately 50% in the case of breast cancer and an almost Complete Response (CR) for ovarian cancer. These early-stage results underline the strong efficacy profile of PF-06647020. The early-stage trials have further demonstrated that PF-06647020, given its low toxicity, is well-tolerated with an acceptable safety profile.

Trial results
To date, 76 patients have been treated with PF-06647020. A total of 60 of which were treated at 2.8 mg/kg once every 3 weeks (Q3W)/cycle in escalating doses from 0.2 – 3.7 mg/kg until progression.

Most adverse events have grade 1-2 with the majority being self-limiting and nor requiring medical intervention. Most commonly (≥10%) reported drug related adverse events included nausea (46%), alopecia (34%), headache (32%), fatigue (30%), neutropenia (26%), vomiting (22%), decreased appetite (17%), myalgia (15%), arthralgia (11%), and diarrhea (11%).

Fourteen patients (18%) experienced Grade ≥3 drug related neutropenia and 3 patients (4%) discontinued due to drug related adverse events.

Twenty-nine recurrent ovarian cancer patients with ECOG Performance Status 0-1 (median age 58.5 yrs [42-77]) were treated at  2.1 mg/kg (1 pt).  Twenty-two patients currently evaluable in this heavily pre-treated group of patients with platinum-resistant ovarian cancer, the trial results showed Complete Response (CR) in 1 patient, 5 patients had Partial Response (PR) with Objective Response Rate (ORR) of 27% (95% CI: 13%, 48%), 12 patients (55%) had Stable Disease (SD), and 4 patients  (18%) had Progressive Disease. Median duration of treatment was 3 cycles (range 1–13). A total of 10 patients remained on treatment.

The investigational drug targets PTK7,  a catalytically inactive protein tyrosine kinase which functions in developmental biology and is over expressed in a variety of human cancers. Exploratory immunohistochemistry staining by a validated assay on archival tumors showed that all ovarian cancer (OVCA) patients in this had PTK7 expression.

Novel approach
PF-06647020 is an anti-PTK7 Antibody-drug Conjugate being developed by Pfizer in collaboration with Stemcentrx (now part of AbbVie). The novel ADC is comprised of a humanized monoclonal antibody directed against PTK7, which is also expressed in many tumor types, linked to an auristatin microtubule inhibitor payload via a cleavable dipeptide linker.

Advanced Solid Tumors
In the phase I study PF-06647020 showed an acceptable safety profile in patients with advanced malignancies, including triple negative breast cancer (TNBC), advanced ovarian cancer and non-small cell lung cancer (NSCLC). PF-06647020 also showed early indication of anti-tumor activity in an unselected patient population. [2]

In data presented during the ESMO/ECCO meeting in 2015, PF-06647020 showed some responses at doses above 2.1mg/kg in patients with advanced triple negative breast cancer and platinum resistant ovarian cancer. At that time, no dose-limiting toxicities (DLTs) were reported with dose escalation continuing to 3.7mg/kg. [2]

“Both triple negative breast cancer and platinum resistant ovarian cancer are difficult to treat, and novel approaches are urgently needed,” noted Markus Joerger, MD, attending medical oncologist at the St. Gallen Cancer Centre (Kantonsspital St.Gallen) in St. Gallen, Switzerland, after reviewing the trial results presented at the annual meeting of the European Society for Medical Oncology. “The clinical activity shown with PF-06647020, is indeed encouraging,” he continued.

“Clinically relevant benefits can be confirmed with some novel targeted agents such as PF-06647020 and it is hoped that their early promise will be confirmed in larger studies,” Joerger concluded.


Last Editorial Review: October 14, 2016

Featured Image: Woman Having Chemotherapy With Nurse Using Digital Tablet Courtesy: © Fotolia. Used with permission. Illustration 1.0: Schematic of PF-06647020 an investigational antibody-drug conjugates targeting PTK7. Courtesy: © Pfizer. Used with permission.

Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

New Anticancer Drugs Show Promise in the Treatment of Solid Tumors

A number of novel anticancer drugs are showing very promising results in the treatment of solid cancers. These cancers, including various forms of lung cancers, breast cancers, ovarian cancer, etc. generally have a high patient base with a high unmet need.

During the biennial European Cancer Congress (ECC 2015), being held in Vienna, Austria (September 25 – 29, 2015) which combines the efforts of the most important European oncology professionals with the aim of improving the prevention, diagnosis, treatment and care of cancer patients, results of a variety of ongoing clinical trials and new treatment options were presented. Among the novel treatment options are a humanized monoclonal antibody, a number of  antibody-drug conjugates or ADC and other (targeted) therapies, including FASN inhibition, and a multi-tyrosine kinase.

ECC2015_2“There are [real good] reasons to be optimistic for breaking new treatments in solid tumors,” Markus Joerger, MD, attending medical oncologist at the St. Gallen Cancer Centre (Kantonsspital St.Gallen) in St. Gallen, Switzerland, noted after reviewing the trial results presented at the 2015 European Cancer Congress.

Refractory/relapsing solid tumors
The results presented are especially interesting for the treatment of difficult to treat cancers and refractory/relapsing solid tumors. “Nasopharyngeal cancer (NPC) is an important cause of cancer deaths in middle-aged patients in Asia, particularly China and Taiwan,” explained Joerger. “Systemic cytotoxic treatment alone is not very effective, but is used concurrently with radiotherapy as a radiosensitiser. For patients relapsing after chemo-radiotherapy, there are currently no effective systemic treatments.”

However, important new findings in the treatment of nasopharyngeal cancer, may offer some hope for patients with an otherwise poor prognosis. “The KEYNOTE-028 clinical trial demonstrated clinical activity of the anti-PD1 monoclonal antibody pembrolizumab (Keytruda®, Merck; formerly MK-3475 and lambrolizumab)  in patients with PD-L1-positive NPC (abstract 2801),” Joerger noted.

“Pembrolizumab is a highly selective, humanised monoclonal antibody against PD-1 that is designed to block the negative immune regulatory signaling of the programmed cell death 1 or PD-1 receptor expressed by T-cells. Future studies will focus on combinatorial immunotherapeutic approaches in patients not responding to anti-PD-(L)1 monoclonal antibodies.”

Triple negative breast cancer
Novel approaches are also on the way in triple-negative breast cancer (TNBC) and platinum-refractory ovarian cancer.

Researchers have found that in solid cancers, in contrast to hematological malignancies, only a limited number of antibody-drug conjugates are internalized.  Due to the limited number of receptors on the cell surface, many trial drugs fail.

Novel antibody-drug conjugates with a variety of MOAs are rapidly changing this. This is especially important in the treatment of patients with triple-negative breast cancer and ovarian cancer.

Commenting on this phenomenon, Joerger observed: “Both diseases are difficult to treat, and novel approaches are urgently needed. Encouraging clinical activity has been shown with PF-06647020, an antibody drug conjugate being developed by Pfizer (late-breaking abstract [LBA] 28). PF-06647020 is comprised of a humanized monoclonal antibody directed against PTK7, linked to an auristatin microtubule inhibitor payload. PTK7 is frequently expressed in solid malignancies,” .

Refractory Small-Cell Lung Cancer
Patients with relapsing or refractory small-cell lung cancer or SCLC have a particularly poor prognosis. High-grade pulmonary neuroendocrine tumors, which includes SCLC, as well as  large cell neuroendocrine carcinoma or LCNEC, represent ~18% of primary lung neoplasms in older patients with a history of smoking.  Today, these cancers remain among the most deadly malignancies.  One of the reasons is that it has been more than 30 years since significant progress has been made in developing viable therapeutic options. But, based on the research presented this year, Joerger noted: “There is hope with Rovalpituzumab Tesirine, an antibody-drug conjugate being developed by Stem CentRx, that targets delta-like 3 or DLL3 which is highly expressed in [human neuroendocrine tumors and their tumor-initiating cells including about] two-thirds of SCLC.” However, DLL3 is not expressed at detectable levels in normal, healthy, tissues.

“In a new phase I clinical study (LBA 7), Rovalpituzumab Tesirine exhibited a good safety profile, and a substantial response rate of 34% in patients with DLL3-positive, relapsed SCLC,” Joerger said.

The DLL3-targeted antibody-drug conjugate Rovalpituzumab Tesirine, also known as Rova-T or SC16LD6.5 is comprised of a humanized anti-DLL3 monoclonal antibody conjugated, via a dipeptide linker, to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin with a drug-to-antibody ratio (DAR) of 2.

In preclinical trials Rovalpituzumab tesirine induced tumor regression and prolonged time to progression significantly outperforming cisplatin (Platinol®, Platinol®-AQ)/etoposide (Toposar®, VePesid®, Etopophos®) in DLL3-expressing SCLC patient-derived xenograft tumor models. Based the promising activity, a first-in-human phase I trial, researchers initiated a first-in-humans clinical trials in patients with recurrent SCLC.

The preliminary phase I study data presented at ECC 2015, for example, confirms that patients with SCLC who were sensitive to first-line combination chemotherapy and were positive for DLL3 gene expression, experienced an objective response rate or ORR of 64%. The data also showed that in the third-line setting, where a standard treatment is currently not available, the ORR in DLL3-expressing patients (n = 15) was 45%. The researchers further confirmed that across all patients in the third-line setting (n = 35), the ORR was 20%.  The researchers found that the trial drug had a manageable toxicity and demonstrated significant anti-tumor activity as a single agent in second- and third-line patients with refractory small-cell DLL3 positive lung cancer.

Tyrosine kinase inhibitor targeting
Tyrosine kinase inhibitor targeting is another innovative approach. “A novel multi-tyrosine kinase inhibitor, entrectinib, targeting TrkA,-B,-C, ROS1 and EML-ALK has been explored in molecularly-selected patients with advanced or metastatic solid tumours (LBA 29),” Joerger said. “Toxicity was manageable, and 10 out of 11 patients harbouring gene rearrangements of NTRK 1/2/3, ROS1 or EML-ALK and receiving entrectinib at the recommended dose experienced a partial tumour response. Targeting NTRK gene rearrangements is a novel approach and could benefit subgroups of patients suffering from e.g. non-small-cell lung cancer (NSCLC).”

Notch3
Researchers are also exploring the use of Notch3 targeting. “The Notch pathway plays an important role in the growth of several solid tumours, including breast and ovarian cancer and melanoma,” explained Joerger. “In particular, Notch3 alterations such as gene amplification and upregulation are associated with poor patient survival. Research using Notch3 targeting as an innovative approach to treat solid malignancies included 27 patients unselected for Notch3 who received increasing doses of the anti-Notch3 antibody-drug conjugate PF-06650808. Responses were seen in two breast cancer patients (LBA 30). While preliminary, targeting Notch3 may become a new treatment approach in patients with selected solid tumours.”

The anti-Notch3 antibody-drug conjugate PF-06650808 is being developed by Pfizer.

Fatty Acid Synthase
Fatty acid synthase or FASN expression increases with tumor progression and is linked with chemoresistance, tumor metastasis, and diminished patient survival in a variety of tumor types.  Based on initial results, researchers believe that FASN inhibition may have anti-tumor activities in a number biologically diverse preclinical tumor models.

Although inhibition of fatty acid synthase or FASN is an entirely original approach to treat solid malignancies, this research provides mechanistic and pharmacologic evidence that FASN inhibition offers a promising therapeutic strategy for treating a solid tumors, including those expressing mutant K-Ras, ErbB2, c-Met, and PTEN.  Joerger explains: “Fatty Acid Synthase of FASN involves the disruption of palmitate biosynthesis and results in apoptosis of tumor cells. The first-in-human study of the first-in-class FASN inhibitor, TVB-2640, led to one partial remission and several long-term disease stabilizations in 31 patients with solid tumours (LBA 27). TVB-2640 proved to be safe when given alone or in combination with paclitaxel mono therapy.” This novel drug is being developed by 3-V Biosciences, based in Menlo Park, CA.

In preclinical studies, 3-V Biosciences’ FASN inhibitor TVB-2640 have shown good tolerability profiles, potent anti-tumor properties in vitro and in vivo, modulation of tumor signaling pathways, alteration of tumor membrane structure and impact on tumor metabolism and strong synergy with paclitaxel.

Early beginnings
Many of the approached mentioned by Joerger are still in early clinical investigation. Further, ongoing, clinical trials designed to evaluate these novel agents will be required to show if these initially encouraging results can be translated into benefits for patients with several solid tumors.


Last Editorial Review: September 28, 2015

Feature Image: Johan Straus Monument in Stadt Park, Vienna, Austria. Feature image Courtesy: © Jorge Royan. This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. CC BY-SA 3.0

Copyright © 2015 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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