On June 4, 2018 CytomX Therapeutics, Inc. (Nasdaq:CTMX) a clinical-stage oncology-focused biopharmaceutical company pioneering a novel class of investigational antibody therapeutics based on its Probody therapeutic technology platform, reported that preliminary clinical results from two arms of the PROCLAIM (PRObody CLinical Assessment In Man) module, PROCLAIM-072 (Press release, CytomX Therapeutics, JUN 4, 2018, View Source [SID1234527137]). PROCLAIM-072 is an ongoing Phase 1/2 trial evaluating CX-072, a Probody therapeutic targeting PD-L1, as monotherapy and in combination with Yervoy (ipilimumab) or Zelboraf (vemurafenib) in patients with advanced, unresectable solid tumors. Data from the CX-072 monotherapy arm and ipilimumab combination arm were presented today in two posters as part of the Developmental Therapeutics—Immunotherapy Session at the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, Illinois.

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"These first clinical results mark a major milestone for CytomX as we advance our Probody platform and introduce a fundamentally new approach to antibody therapeutic drug development," said Sean McCarthy D.Phil., president and chief executive officer of CytomX Therapeutics. "The findings presented today show that our lead wholly-owned program, the PD-L1 targeting Probody therapeutic, CX-072, has the potential to become a new centerpiece of combination cancer therapy. These preliminary results suggest that CX-072 as monotherapy and in combination with ipilimumab has a favorable safety profile and encouraging antitumor efficacy in late-stage, heavily pretreated cancer patients. Moreover, these clinical data check important boxes for the development of our core platform technology by showing that CX-072 remains stable in circulation over extended periods of dosing and elicits anti-tumor effects within the tumor microenvironment. Based on these initial results, we have initiated multiple monotherapy expansion cohorts to further explore the safety and efficacy of this potentially differentiated PD-L1 inhibitor."

Preliminary Results of the First-In-Human, Dose-Finding PROCLAIM-072 Trial of the PD-L1 Probody Therapeutic CX-072 as Monotherapy in Patients with Advanced Solid Tumors

Session: Developmental Therapeutics—Immunotherapy (Poster #285)
Presenter: Karen A. Autio, M.D., MSc., Memorial Sloan Kettering Cancer Center

The primary objectives of this first-in-human, dose-escalation, monotherapy arm are to assess safety and tolerability, including determination of the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of CX-072 as monotherapy. At the completion of escalation, the arm had enrolled 22 patients, with an average of four prior anti-cancer treatments in a variety of tumor types for which no anti-PD-1 or anti-PD-L1 agents are available for their disease. Patients received escalating doses of CX-072 from 0.03 mg/kg to 30 mg/kg. Enrollment is complete and patient follow-up is ongoing.

Monotherapy Well Tolerated

The maximum tolerated dose (MTD) was not reached. As of an April 20, 2018 data cutoff, results showed that the administration of monotherapy CX-072 was well tolerated with the majority of treatment-related adverse events (TRAEs) as Grade 1/2. Grade 3/4 TRAEs were reported in two patients: neutropenia and thrombocytopenia in a patient with thymic cancer (3 mg/kg) and transaminase elevation in a patient with breast cancer (30 mg/kg). Both events were successfully managed with therapeutic intervention including steroids and discontinuation of CX-072.

Evidence of Activity

As of an April 20, 2018 data cutoff, results showed that among 20 evaluable patients who received CX-072, objective responses by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a commonly used guideline for evaluating tumors, were observed in 3 (15%) patients: thymoma (unconfirmed PR (uPR); 3 mg/kg), PD-L1 negative TNBC (confirmed PR; 10 mg/kg) and cervical cancer (uPR; 10 mg/kg) (all partial responses (PR)). Stable disease was observed in 8 patients (40%) for a disease control rate of 55%. Decreased target lesions were observed in 42% (8/19) of all evaluable patients with measurable disease at baseline and in 60% (6/10) of the subset of patients who received > 3 mg/kg of CX-072. Two of the responders were still on treatment (8 months each) at the time of the data cutoff.

Evidence of Probody Platform Performance

Results from a preliminary single-dose pharmacokinetic analysis of single-agent CX-072 suggest that, as designed, CX-072 circulates predominantly as the intact masked prodrug across all dose levels. Further, CX-072 is only minimally influenced by target mediated drug disposition at low doses, suggesting that masking is effective in blocking interaction with PD-L1 in the periphery.

Based on these preliminary safety, efficacy and translational data, further evaluation of CX-072 monotherapy (10 mg/kg every two weeks) is now underway in 8 expansion cohorts in a variety of cancer types.

Preliminary Interim Results of the First-In-Human, Dose-Finding PROCLAIM-072 Trial of the PD-L1 Probody Therapeutic CX-072 in Combination with Ipilimumab in Patients with Advanced Solid Tumors

Session: Developmental Therapeutics—Immunotherapy (Poster #286)
Presenter: Rachel E. Sanborn, M.D., Earle A. Chiles Research Institute, Providence Cancer Center

The primary objectives of this ongoing arm of the study are to assess safety and tolerability, and to determine the MTD and DLT of CX-072 when administered in a concomitant combination schedule with ipilimumab. At the April 20, 2018 data cutoff, the study had enrolled 16 immunotherapy naïve patients who had received an average of four prior anti-cancer treatments in a variety of tumor types for which no anti-PD-1 or PD-L1 agents were available for their disease. Patients received the combination ipilimumab (3 mg/kg) and CX-072 (escalating doses of 0.3 mg/kg to 10 mg/kg) every three weeks for four cycles followed by monotherapy CX-072 every two weeks.

Combination with Ipilimumab Well Tolerated

As of the April 20, 2018 data cutoff date, the MTD had not yet been reached and no new safety signals were observed beyond those expected for each component of the ipilimumab plus CX-072 combination. The majority of TRAEs were Grade 1/2. Of the 16 treated patients, 5 (31%) reported a Grade 3/4 TRAE, a rate similar to that reported previously for 3 mg/kg ipilimumab monotherapy1. These events included: Grade 3 colitis (n=1), Grade 3 dyspnea/pneumonitis (n=1), Grade 3 headache/Grade 3 hyponatremia (n=1), and Grade 3 amylase/Grade 4 lipase (n=1)2. A dose limiting toxicity of Grade 3 dyspnea was reported in one patient. The study is still ongoing with enrollment and dose escalation continuing.

Evidence of Activity

As of an April 20, 2018 data cutoff, results also showed that among 12 evaluable patients who received ipilimumab (3 mg/kg) combined with CX-072 (0.3 to 10 mg/kg), 3 (25%) achieved objective responses by RECIST v1.1, including patients with: anal cancer (confirmed complete response (CR); 0.3 mg/kg CX-072), testicular cancer (uPR; 1 mg/kg CX-072) and cancer of unknown primary (uPR; 3 mg/kg CX-072). Stable disease was observed in 8% of patients for a disease control rate of 33%. All 3 of the responders remained on treatment (10, 6 and 5 months, respectively) at the data cutoff.

Preliminary Single-Dose Clinical Pharmacokinetics of an anti-PD-L1 Probody Therapeutic in Cancer Patients
ASCO Supplement of the Journal of Clinical Oncology [J Clin Oncol 36, 2018 (suppl; abst 214558)]. (Abstract #e14558)

Preliminary pharmacokinetic clinical data showed that single-agent, single-dose CX-072 behaved as designed and circulated predominantly as the intact antibody prodrug and is only minimally affected by target-mediated drug disposition, consistent with being effectively masked in circulation.

Conference Call and Webcast

CytomX will host a conference call and live webcast with slides today, Monday, June 4, 2018, beginning at 5:00 p.m. CT/ 6:00 p.m. ET to discuss these data presentations. This event can be accessed in three ways:

From the CytomX website: View Source Please access the website 15 minutes prior to the start of the call to download and install any necessary audio software.

By telephone: Participants can access the call by dialing 1-877-809-6037 (United States) or 1-615-247-0221 (International) referencing Conference ID 4294667.

By replay: A replay of the webcast will be located under the Investor Relations section of CytomX’s website approximately two hours after the conclusion of the live call and will be available for 30 days following the call.
About PROCLAIM

PROCLAIM (Probody Clinical Assessment In Man) is an international umbrella program designed to evaluate CytomX’s Probody therapeutics. The first module is the PROCLAIM-CX-072 clinical program, an open-label, dose-finding Phase 1/2 trial evaluating CX-072 as monotherapy and in combination with Yervoy (ipilimumab) or Zelboraf(vemurafenib) in patients with metastatic or locally advanced unresectable solid tumors or lymphomas. CytomX aims to achieve three goals as part of the PROCLAIM-072 clinical trial:

Tolerability: Demonstrate that CX-072 is well tolerated in patients and potentially improves safety, particularly in the combination setting.
Anti-cancer activity: Demonstrate initial evidence of CX-072’s anti-cancer activity as monotherapy and in combination.
Translational program and Probody platform proof-of-concept: Explore mechanistic aspects of Probody activity in patients as observed in preclinical models.

On June 4, 2018 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Sanofi reported that pivotal data from two trials evaluating cemiplimab in advanced cutaneous squamous cell carcinoma (CSCC) were published today in the New England Journal of Medicine (NEJM) and presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Regeneron, JUN 4, 2018, View Source [SID1234527153]). Advanced CSCC, the deadliest nonmelanoma skin cancer, encompasses both patients with metastatic CSCC and those with locally advanced CSCC who are not candidates for surgery; there is currently no approved treatment for these patients. Cemiplimab is an investigational human monoclonal antibody targeting the immune checkpoint PD-1 (programmed cell death protein 1).

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"The strong results seen with cemiplimab are noteworthy given that advanced CSCC is a very serious condition that currently has no approved treatments once surgery is no longer an option," said Michael R. Migden, M.D., co-lead author and Associate Professor in the Departments of Dermatology and Head and Neck Surgery at The University of Texas MD Anderson Cancer Center. "Advanced CSCC tumors were shown to be responsive to cemiplimab in both metastatic and locally advanced patients, with the results being clinically meaningful and consistent between the Phase 1 and Phase 2 trials."

Data published in NEJM and/or presented at ASCO (Free ASCO Whitepaper), and confirmed by independent central review, include:

Phase 2 EMPOWER-CSCC-1 trial:
Cemiplimab-treated patients had a 47.5 percent response rate (28 of 59 patients, including 4 complete responses and 24 partial responses [PRs]) with a median observed time to response of 2 months as of the data cut-off date. The durable disease control rate (DCR) was 61 percent (36 of 59 patients) and was defined as the proportion of patients without progressive disease for at least 105 days.
The median duration of response (DOR), median progression free survival, and median overall survival have not been reached as of the data cut-off date (median follow-up for all patients: 8 months). Of the responding patients, 82 percent remained in response and continued on cemiplimab. The estimated progression-free probability at 12 months was 52.5 percent, and the estimated probability of survival at 12 months was 81 percent.
The most common treatment-emergent adverse events were diarrhea (27 percent), fatigue (24 percent), nausea (17 percent), constipation and rash (each 15 percent). Grade 3 or higher adverse events regardless of attribution were reported in 25 patients (42 percent), of whom seven (12 percent) were considered related to treatment. Three patients (5 percent) had adverse events with the outcome of death; however, none were considered related to treatment.
Data are from 59 metastatic CSCC patients who received cemiplimab (3 mg/kg every 2 weeks) for up to 96 weeks.
CSCC expansion cohorts of Phase 1 trial:
Cemiplimab-treated patients had a response rate of 50 percent (13 of 26 patients, all of which were PRs) with a median observed time to response of 2 months as of the data cut-off date. The durable DCR was 65 percent (17 of 26 patients). The median DOR has not been reached as of the data cut-off date (median follow-up for all patients: 11 months).
The most common treatment-emergent adverse events of any grade were fatigue (27 percent), constipation, decreased appetite, diarrhea, hypercalcemia, hypophosphatemia, nausea and urinary tract infection (each 15 percent). Grade 3 or higher adverse events regardless of attribution were reported in 12 patients (46 percent), of which five (19 percent) were considered related to treatment. Two patients (8 percent) had adverse events related to treatment that led to treatment discontinuation.
Data are from 26 advanced CSCC patients who participated in two Phase 1 expansion cohorts and received cemiplimab (3 mg/kg every 2 weeks) for up 48 weeks. Patients either had metastatic CSCC or locally advanced CSCC who were not candidates for surgery.
These findings formed part of the data set used for regulatory applications for cemiplimab as a potential treatment for advanced CSCC. These applications were accepted earlier this year for priority review by the U.S. Food and Drug Administration (FDA) and review by the European Medicines Agency (EMA). The FDA target action date is October 28, 2018, and the EMA review process is expected to be complete by the first half of 2019. Regulatory applications in additional countries are also being considered for submission later in 2018. There are currently no FDA- or EMA-approved treatments for patients with metastatic CSCC or patients with locally advanced CSCC who are not candidates for surgery.

Cemiplimab is being jointly developed by Regeneron and Sanofi under a global collaboration agreement, and was invented by Regeneron using the company’s proprietary VelocImmune technology that yields optimized fully-human antibodies. In addition to CSCC, cemiplimab is also being investigated in potentially pivotal/pivotal trials in non-small cell lung cancer, basal cell carcinoma and cervical cancer alongside exploratory trials in squamous cell carcinoma of the head and neck, melanoma, colorectal cancer, prostate cancer, multiple myeloma, Hodgkin lymphoma and non-Hodgkin lymphoma.

Cemiplimab is currently under clinical development, and its safety and efficacy have not been evaluated by any regulatory authority.

About CSCC
CSCC is the second most common type of skin cancer in the U.S., accounting for approximately 20 percent of all skin cancers and with the number of newly diagnosed cases expected to rise annually. Although CSCC has a good prognosis when caught early, the cancer can prove especially difficult to treat effectively when it is advanced, and patients can experience reduced quality of life due to the impact of the disease as it progresses. Advanced CSCC is the deadliest non-melanoma skin cancer. While estimates vary, sources suggest that between 4,000 to 8,000 people in the U.S. die annually of advanced CSCC.

About Regeneron Pharmaceuticals, Inc.
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents life-transforming medicines for people with serious diseases. Founded and led for 30 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to six FDA-approved treatments and numerous product candidates in development, all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye disease, heart disease, allergic and inflammatory diseases, pain, cancer, infectious diseases and rare diseases.

Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite technologies, such as VelocImmune which produces optimized fully-human antibodies, and ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world.

1stOncology’s ‘Commercial Interests at ASCO (Free ASCO Whitepaper) 2018‘ report highlights the landscape of commercial oncology drug development presenting abstracts at the 2018 ASCO (Free ASCO Whitepaper) meeting. Below is some interesting headline points our analyst team picked from ASCO (Free ASCO Whitepaper) 2018, but if you would like to get the full picture, we invite you to 48 hours of free access to our ASCO (Free ASCO Whitepaper) 2018 whitepaper. Sign up here for your free access.

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Five Interesting Startups Presenting Abstracts at ASCO (Free ASCO Whitepaper) 2018:

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On June 3, 2018 FibroGen, Inc. (NASDAQ: FGEN), a biopharmaceutical company, reported Phase 1/2 clinical trial results of pamrevlumab in combination with standard-of-care chemotherapy in patients with locally advanced unresectable pancreatic cancer (LAPC) (Press release, FibroGen, JUN 3, 2018, View Source [SID1234527124]). . Principal investigator Vincent J. Picozzi, Jr., M.D., Director, Pancreas Center of Excellence, Virginia Mason Cancer & Digestive Diseases Institutes, presented the results in a discussion poster session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. Pamrevlumab is a proprietary first-in-class antibody targeting connective tissue growth factor (CTGF) under development for the treatment of fibrosis and fibroproliferative disorders.

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"These are some of the most exciting clinical trial results in locally advanced pancreatic cancer I have seen since I began treating pancreatic cancer patients," said Dr. Picozzi. "The data suggest that pamrevlumab in combination with chemotherapy has the potential to become a neoadjuvant treatment regimen for locally advanced unresectable pancreatic cancer patients that has not existed before."

Patients with locally advanced pancreatic cancer (without metastasis) tend to have a poor prognosis with a median survival of 9–18 months. In patients who have undergone resection of their tumor, median survival and five-year survival rates have been reported to be higher than those without resection. Therefore, treatment to achieve a surgical resection in this patient population is a meaningful treatment goal to potentially achieve a favorable overall survival outcome.

In this open-label, randomized Phase 1/2 study, pamrevlumab was administered in combination with standard-of-care chemotherapy (gemcitabine and nab-paclitaxel) and compared to treatment with chemotherapy alone in patients with locally advanced pancreatic ductal adenocarcinoma, who were not eligible for surgical resection based on histology, computerized tomography (CT) scans, and laparoscopy criteria, prior to randomization. Upon completion of the six months of study drug treatment, patients underwent surgical eligibility assessment based on pre-specified objective criteria. The study enrolled 37 patients: 24 received pamrevlumab + chemotherapy: 13 received chemotherapy alone.

At ASCO (Free ASCO Whitepaper) 2018, FibroGen reported that a higher proportion of patients whose tumor was previously considered unresectable became eligible for resection (based on protocol pre-specified post-treatment surgical eligibility criteria) after receiving pamrevlumab and chemotherapy than after receiving chemotherapy alone (at the end of 6 months of treatment), 70.8% vs. 15.4%. For those patients who met these surgical resection eligibility criteria at post-treatment assessment, individual patient condition and circumstance contributed to whether resection subsequently occurred. A higher proportion of pamrevlumab-treated patients achieved surgical resection than those received chemotherapy alone, 33.3% vs. 7.7%.

In the study, patients were followed for survival after evaluation for eligibility for resection and, when applicable, after resection. Patients who had successful resections in this study had a statistically significant longer median survival benefit as compared to patients who did not undergo resection, 40 months vs.18.6 months (p=0.0141), as of May, 2018. FibroGen is continuing to monitor study patients for survival.

"Patients with unresectable locally advanced pancreatic cancer are in need of an innovative and effective treatment with the potential to transform non-operable cancer into resectable disease," said Elias Kouchakji, M.D., Senior Vice President, Clinical Development and Drug Safety. "The updated clinical results we are reporting at ASCO (Free ASCO Whitepaper) suggest that pamrevlumab may improve the treatment outcomes for patients who are currently deemed unresectable."

About Locally Advanced Pancreatic Cancer

In locally advanced pancreatic cancer (LAPC), tumors typically encase structures, particularly blood vessels that are closely associated with the pancreas such as the superior mesenteric artery and superior mesenteric vein. Involvement of the cancer around these blood vessels precludes surgical removal of the tumor. Approximately 80% of newly diagnosed LAPC patients are classified as having unresectable disease, and patients with unresectable LAPC have a median survival only slightly better than that of patients with metastatic pancreatic cancer. Patients with resectable cancer whose tumors are surgically removed have a much better prognosis, with median survival of approximately 23 months, and some patients being cured.

About Pamrevlumab

Pamrevlumab is a first-in-class antibody developed by FibroGen to inhibit the activity of connective tissue growth factor (CTGF), a common factor in fibrotic and proliferative disorders characterized by persistent and excessive scarring that can lead to organ dysfunction and failure. Pamrevlumab is advancing towards Phase 3 clinical development for the treatment of idiopathic pulmonary fibrosis (IPF) and pancreatic cancer, and has been granted Orphan Drug Designation (ODD) in each of these indications, and is currently in a Phase 2 trial for Duchenne muscular dystrophy (DMD). Pamrevlumab recently received Fast Track designation from the U.S. Food and Drug Administration for the treatment of patients with locally advanced unresectable pancreatic cancer. Pamrevlumab has demonstrated a good safety and tolerability profile in multiple Phase 2 trials conducted to date. For information about pamrevlumab studies currently recruiting patients, please visit www.clinicaltrials.gov.

On June 3, 2018 Polaris Group reported results from a phase 1 clinical study, showing that Polaris lead therapeutic candidate ADI‑PEG 20 in combination with FOLFOX demonstrated promising efficacy for heavily pre-treated hepatocellular carcinoma (HCC) patients (Press release, Polaris Pharmaceuticals, JUN 3, 2018, View Source [SID1234527209]). The results were presented by Dr. James Harding from Memorial Sloan Kettering Cancer Center at the American Society Clinical Oncology’s 2018 annual meeting.

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Overall, 38 HCC patients who have failed at least one line of prior systemic treatment were enrolled and a partial response (PR) was observed in 8 (21.0%), including two in Taiwan. Of the 38, 21 had failed at least two lines of prior systemic treatment, and PRs were observed in 5/21 (23.8%). Currently, all 5 of the third-line or later PR patients are still alive, with 4 of 5 still undergoing treatment and 2 having now maintained a PR for over two years; thus suggesting responses can potentially be durable.

Side effects of the combination have been what would be expected for FOLFOX only, except for injection site reactions consistent with ADI‑PEG 20’s intramuscular route of administration.

Given these encouraging results, a meeting was held with the United States Food & Drug Administration (FDA). Based on this meeting, the study has been expanded into a global, phase 2, single-arm study to support accelerated approval for HCC patients who have failed at least two lines of prior systemic therapies. This study is currently enrolling patients in the US and Taiwan, and will be expanded into UK, Italy, Korea and China.

"ADI‑PEG 20 plus FOLFOX is showing more favorable efficacy compared to historic controls and the combination remains well tolerated. We appreciate the helpful comments of the FDA in assisting us to craft the phase 2 portion of this protocol", said John Bomalaski, M.D., Executive Vice President, Medical Affairs, of Polaris. "We now have a number of clinical trials underway with ADI‑PEG 20 in combination with standard of care agents in multiple cancer indications. These other studies have also shown that ADI‑PEG 20 in combination with multiple chemotherapy agents is well tolerated, and highly improves response rates. We are committed to developing an effective treatment for the 3rd-line or later HCC patients who have no approved treatment option", he added.

About ADI‑PEG 20

ADI‑PEG 20 is a biologic being developed by Polaris Group to treat cancers carrying a major metabolic defect that renders them unable to internally synthesize arginine. Because arginine is essential for protein synthesis and survival of cells, these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI‑PEG 20 is designed to deplete the external supply of arginine, causing arginine-dependent cancer cells to die while leaving the patient’s normal cells unharmed. Multiple cancers have been reported to have a high degree of arginine-dependency and can potentially be treated with ADI‑PEG 20.