On June 4, 2018 Bristol-Myers Squibb Company (NYSE:BMY) reported updated results from the Phase 3 CheckMate -238 trial evaluating Opdivo (nivolumab) versus Yervoy (ipilimumab) in patients with stage IIIB/C or stage IV melanoma who are at high risk of recurrence following complete surgical resection (Press release, Bristol-Myers Squibb, JUN 4, 2018, View Source [SID1234527123]). In updated results from the study, Opdivo continued to demonstrate statistically longer recurrence-free survival (RFS) of 62.6%, the primary endpoint of the study, versus 50.2% for Yervoy (HR: 0.66, P<0.0001) at a minimum follow-up of 24 months across key subgroups, including disease stages and BRAF mutation status.

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No new safety data were generated as part of the 24-month analysis. As previously reported from the 18-month analysis, Opdivo demonstrated a significantly lower rate of adverse events (AEs) leading to discontinuation (9.7% of patients in the Opdivo arm compared to 42.6% of patients in the Yervoy arm) and treatment-related grade 3/4 AEs (14.4% of patients in the Opdivo arm compared to 45.9% in the Yervoy arm).

Findings will be presented on Monday, June 4 from 8:24-8:36 AM CDT during the Melanoma/Skin Cancers session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2018 in Chicago (Abstract #9502).

"The broader use of Immuno-Oncology agents has changed the cancer treatment landscape and, with advances in research, we have been able to extend the use of these agents to adjuvant therapy in melanoma in order to help prevent disease recurrence," noted Jeffrey S. Weber, M.D., Ph.D., principal investigator of CheckMate -238. "Results from the study’s 24-month follow-up, the longest follow-up of any PD-1 inhibitor in the adjuvant setting, continue to strongly support the benefit of nivolumab across multiple stages of melanoma and BRAF mutation status."

Arvin Yang, M.D., Ph.D., development lead, melanoma and genitourinary cancers, Bristol-Myers Squibb, said, "The updated CheckMate -238 data continue to show that adjuvant treatment can change the course of melanoma by preventing relapse and progression to an advanced stage."

Additional Data from CheckMate -238 at ASCO (Free ASCO Whitepaper) 2018

In the study, Opdivo demonstrated superior RFS versus Yervoy, regardless of disease stage, PD-L1 expression or BRAF mutation status, with RFS rates of 62.6% with Opdivo compared to 50.2% with Yervoy in the intent-to-treat patient population. In patients with stage IIIB melanoma, RFS rates at 24 months for Opdivo were 70.8% versus 60.7% with Yervoy; for patients with stage IIIC melanoma, RFS rates were 58.0% with Opdivo versus 45.4% with Yervoy; and for patients with stage IV melanoma, RFS rates for Opdivo were 58.0% versus 44.3% with Yervoy. In patients with BRAF mutant melanoma, RFS rates for Opdivo were 61.9% versus 51.7% with Yervoy; in patients with BRAF wild-type melanoma, Opdivo demonstrated a RFS of 63.5% versus 46.2% with Yervoy.

About CheckMate -238

CheckMate -238 is an ongoing Phase 3, randomized double-blind study of Opdivo versus Yervoy in patients who have undergone complete resection of stage IIIB/C or stage IV melanoma. The trial randomized 906 patients 1:1 to receive either Opdivo 3 mg/kg every two weeks (n=453) or Yervoy 10 mg/kg (n=453) every three weeks for four doses and then every 12 weeks starting at week 24. Patients were treated until disease recurrence, unacceptable toxicity or withdrawal of consent for up to one year. The primary endpoint is RFS, defined as the time between randomization and the date of first recurrence, new primary melanoma or death. After meeting the primary endpoint, the trial will continue to evaluate for overall survival, a secondary endpoint.

Adjuvant Therapy in Melanoma

Melanoma is separated into five staging categories (stages 0 to 4) based on the in-situ feature, thickness and ulceration of the tumor, whether the cancer has spread to the lymph nodes, and how far the cancer has spread beyond lymph nodes.

Stage III melanoma has reached the regional lymph nodes but has not yet spread to distant lymph nodes or to other parts of the body (metastasized), and requires surgical resection of the primary tumor as well as the involved lymph nodes. Some patients may also be treated with adjuvant therapy. Despite surgical intervention and possible adjuvant treatment, most patients experience disease recurrence and progress to metastatic disease. By five years, the majority of stage IIIB and IIIC patients (68% and 89%, respectively) experience disease recurrence.

On June 4, 2018, a poster titled "Pharmacodynamics and Genomic Profiling of Patients Treated With Cabiralizumab + Nivolumab Provide Evidence of On-Target Tumor Immune Modulations and Support Future Clinical Applications" was presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Presentation, Five Prime Therapeutics, JUN 4, 2018, View Source [SID1234527139]).

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On June 4, 2018 SELLAS Life Sciences Group, Inc. (NASDAQ:SLS) ("SELLAS" or "the Company") reported that interim Phase 1 data of GPS in combination with nivolumab in patients with WT1+ ovarian cancer in second or third remission after salvage chemotherapy at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Sellas Life Sciences, JUN 4, 2018, View Source [SID1234527155]). The presentation, "A phase I study of concomitant galinpepimut-S (GPS) in combination with nivolumab (nivo) in patients (pts) with WT1+ ovarian cancer (OC) in second or third remission," is being delivered by Roisin E. O’Cearbhaill, M.D., Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, during the "Gynecologic Cancer" session from 1:15 to 4:45 p.m. CT. The primary endpoint of the study is safety and assessment of toxicity, and treatment is continued until disease progression or toxicity. The secondary endpoint is immune response, and the exploratory endpoints include landmark 1-year PFS rate compared to historical controls and correlative analyses between clinical and immune responses.

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Exploratory efficacy interim data from this open-label Phase 1 investigator-sponsored trial showed that GPS, when combined with a PD-1 inhibitor, demonstrated PFS of 64% at one year in an intent to treat (ITT) group of 11 evaluable patients with WT1+ ovarian cancer in second or greater remission. Among patients who received at least three doses of GPS in combination with nivolumab, PFS at one year was 70% (7/10). The historical rates with best standard treatment do not exceed 50% in this disease setting. The most common adverse events were Grade 1 or 2, including fatigue and injection site reactions. Dose limiting toxicity was observed in one patient, following the second dose of the combination. No additional adverse event burden was observed for the combination as compared to nivolumab monotherapy. WT1 is a tumor antigen that is expressed in about half of ovarian cancers. The combination induced a high frequency of T- and B-cell immune responses.

Based on these safety, clinical activity and immunogenicity data, SELLAS expects to initiate a Phase 1/2 clinical study of GPS in combination with the PD-1 inhibitor pembrolizumab in a variety of tumor types, including WT1+ ovarian cancer in the third quarter of 2018.

"Patients with advanced relapsed ovarian cancer, in which WT1 is highly expressed, have few treatment options with limited efficacy," said Angelos Stergiou, MD, ScD h.c., President & Chief Executive Officer of SELLAS. "The interim data being presented today further support the therapeutic potential of GPS in high-risk cancer populations, including ovarian cancer. In this Phase 1 trial, the combination of GPS and nivolumab showed promising clinical and immune response activity with no additional adverse event burden as compared to nivolumab monotherapy, warranting further evaluation. These data bolster our commitment to developing GPS, alone and in combination, across a wide range of cancers, and we look forward to initiating our Phase 1/2 basket trial investigating the combination of GPS with pembrolizumab in five WT1+ tumor types, including ovarian, small cell lung, colorectal and triple negative breast cancer and acute myeloid leukemia."

Of the 11 patients evaluated:

7 patients were in second remission and 4 patients were in third remission
10 patients received six total doses of GPS (800 mcg) over 12 weeks in combination with seven infusions of I.V. nivolumab (3 mg/kg) over 14 weeks
all underwent toxicity assessments with each dose of GPS, and three weeks after the completion of therapy at Week 15. Non-progressors at Week 15 were permitted to receive four additional GPS doses, administered every eight weeks.
With regard to clinical and immune responses:

in 11 evaluable patients, the landmark 1-year PFS rate was 64% in the ITT group and 70% in the ten patients who received at least three doses of GPS + nivolumab. Historical rates do not exceed 50% in this disease setting
serum levels of antigen-specific IgG, against both individual WT1 peptides within GPS and the full-length WT1 protein, were induced in 86% of patients
achievement of high titers of WT1-specific IgG post-GPS results from Immunoglobulin (Ig) M to IgG class switching, the latter being a surrogate marker of induction of activated T-helper (Th) cells after vaccination
antigen-specific T-cell responses to individual WT1 peptides were observed between Weeks 6-15, primarily CD4 T-cells and, to a smaller extent, CD8 T-cells
"Effective consolidation or maintenance strategies are needed to prevent further recurrence or to prolong remission in patients with ovarian cancer after successful salvage from a previous relapse. In this setting, immune-directed therapy with a combination of blocker nivolumab and GPS, a multivalent, heteroclitic peptide vaccine targeting WT1, an antigen expressed in about half of ovarian cancers, led to high rates of antigen-specific immunization. We anticipate that this enhanced immunogenicity will translate into a reduction in relapses in larger studies," mentioned Dr. O’Cearbhaill. She added "these encouraging interim data suggest that the combination of GPS plus PD-1 inhibitors deserves further study in WT1+ ovarian cancer."

About Galinpepimut-S (GPS):
GPS is a heteroclitic multivalent, multi-peptide cancer immunotherapeutic agent composed of four peptides, addressing over 20 epitopes, and derived from the WT1 protein, which has been ranked by the National Cancer Institute as a top priority among cancer antigens for immunotherapy. Importantly, because the WT1 antigen is overexpressed in many malignancies, and is not found in most normal tissues, GPS has the potential to be a broad immunotherapy, effective across a multitude of diverse cancer types and patient populations.

On June 4, 2018 At the American Society Clinical Oncology’s 2018 annual meeting, scientists from National Institute of Cancer Research Taiwan reported results from a phase 1 clinical study, showing that Polaris lead therapeutic candidate ADI‑PEG 20 in combination with pembrolizumab has activity for advanced solid tumors (Press release, Polaris Pharmaceuticals, JUN 4, 2018, View Source [SID1234527208]).

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The study results showed that ADI‑PEG 20 could be safely combined with pembrolizumab at its full dose (200 mg) for the treatment of advanced solid tumors. In the dose escalation cohort, two patients, one with thymus cancer and one with nasopharyngeal carcinoma, both in the fourth-line systemic treatment, had a partial response (PR). The main toxicity has been transient and manageable neutropenia. The study is currently enrolling patients in two recommended phase 2 dose cohorts: one for advanced cancers with low PD-L1 expression and one for head and neck cancer. Overall, the study has an objective response rate (ORR) of 27.8% (5/18) in evaluable patients at this time.

In the advanced cancers with low PD-L1 expression cohort, only patients with less than 50% PD-L1 expression are eligible for entry. Of the first 8 evaluable patients in this group, the current ORR is 37.5% as 3 PRs have been observed in heavily pre-treated patients: a third-line mucosal melanoma, a fifth-line cholangiocarcinoma and a fourth-line esophageal carcinoma. These preliminary results suggest that ADI-PEG 20 could potentially be synergistic with program death compounds, and various combinations that include ADI‑PEG 20 and other immunotherapies should be further explored in multiple cancer types.

"Preclinical data indicated that ADI‑PEG 20 could up-regulate PD-L1 expression, turning immune ‘cold’ tumors to express PD-L1 and thus more receptive to programmed death inhibition with agents such as pembrolizumab. We are gratified to see this same scenario occur in patients," said John Bomalaski, M.D., Executive Vice President, Medical Affairs, of Polaris. "Based on this encouraging data, we now have multiple trials planned with ADI‑PEG 20 and various checkpoint inhibitors, including combinations with both programmed death and CTLA-4 inhibitors. The enhancement of sensitivity to programmed death inhibition, combined with ADI-PEG 20’s efficacy, tolerability, and different mechanism of action make it an ideal agent for incorporation into checkpoint agent therapy," 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.

On June 4, 2018 Patients with metastatic uveal melanoma (mUM) treated with IMCgp100 continued to experience a durable tumour response with a median follow up of 19.1 months, without yet reaching median overall survival (OS), according to new Phase I research to be reported at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.2 IMCgp100 is the wholly-owned, lead programme from Immunocore Limited, a leading T-cell receptor (TCR) company focused on delivering first-in-class biological therapies that transform lives (Press release, Immunocore, JUN 4, 2018, View Source [SID1234527140]).

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Although rare, uveal melanoma is the most common form of adult eye cancer.3 When it metastasises beyond the eye, less than half of patients will survive for one year.4 Of the 19 HLA-A*0201+ patients enrolled in Phase I of the Phase I/II dose escalation trial, 17 were evaluated for efficacy. Among these patients, treatment with IMCgp100 was associated with an objective response rate of 18% (90% confidence interval [4,30]) and a one-year overall survival rate of 74% (95% confidence interval [48,88]) at the time of data cut-off.2

"Survival rates in uveal melanoma have remained largely unchanged for decades, and it is difficult to treat once it advances to metastatic disease," said Dr. Takami Sato, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University and lead investigator. "These data provide compelling evidence that IMCgp100 may offer hope to this underserved patient population."

Additional exploratory survival analyses also indicated prolonged OS was associated with a number of pharmacodynamic outcomes, including lymphocyte trafficking, providing encouraging evidence supporting the proposed mechanism of action of IMCgp100.2

"Immunocore is focused on transforming the lives of patients with some of the most challenging diseases, such as metastatic uveal melanoma, for which there is currently no standard of care," said Andrew Hotchkiss, Chief Executive Officer at Immunocore. "Although these are early findings, we are encouraged by the emerging clinical data and focused on advancing our pivotal trials."

The most common adverse events in the Phase I arm included pruritus (severe itching of the skin; 90%), pyrexia (fever) and fatigue (84%), and hypotension (74%).2 Dose limiting toxicities were observed in 3 patients; all were reversible abnormalities in liver function tests (Grade 3 or 4 ALT/AST changes). There were no IMCgp100-related AEs that resulted in discontinuation or death.2

About Metastatic Uveal Melanoma
Uveal melanoma is an aggressive form of melanoma which affects the eye, with a poor prognosis and no standard of care.5 Although it is the most common primary intraocular malignancy in adults,3 the diagnosis is rare, with approximately 4,000 new patients diagnosed globally each year (1,500 cases/year in US).1 Up to 50% of people with uveal melanoma will eventually develop metastatic disease.5,6 When the cancer spreads beyond the eye, only approximately 40% of patients will survive for one year.4

About the IMCgp100-102 Phase I/II Trial
In this study, IMCgp100 is administered on a weekly basis with an intra-patient escalation dosing regimen. The dose escalation portion of the study has been completed, which identified the recommended Phase II intra-patient dose. The Phase II portion of the study is ongoing evaluating both the safety and efficacy in patients with metastatic uveal melanoma. The currently enrolling cohort is assessing IMCgp100 in patients who have experienced disease progression after 1 or 2 prior lines of therapy, which may include up to 1 line of liver directed therapy. Approximately 150 patients will be enrolled in the Phase II portion and the estimated enrolment completion date is September 2019.

About the IMCgp100 Programme
IMCgp100 is a novel bi-specific biologic T cell redirection therapy that specifically targets the melanoma-associated antigen gp100, and which is now in pivotal studies for mUM. IMCgp100 was granted Orphan Drug Designation by the US Food and Drug Administration in 2016 and Promising Innovative Medicine designation under UK Early Access to Medicines Scheme in 2017. For more information about enrolling IMCgp100 clinical trials for metastatic uveal melanoma, please visit ClinicalTrials.gov (NCT02570308, NCT03070392).

About ImmTAC Molecules
Immunocore’s proprietary TCR (T Cell Receptor) technology generates a novel class of bi-specific biologics called ImmTAC (Immune mobilising monoclonal TCRs Against Cancer) molecules that enable the immune system to recognise and kill cancerous cells. ImmTAC molecules are based on synthetic, soluble TCRs engineered to recognise intracellular cancer antigens with ultra-high affinity and selectively kill cancer cells via an anti-CD3 immune-redirecting effector function. ImmTAC molecules can access up to nine-fold more target antigens than typical antibody-based approaches, including monoclonal antibodies. Based on the demonstrated mechanism of T cell infiltration into human tumours, the ImmTAC mechanism of action holds the potential to tackle solid "cold" low mutation rate tumours, the majority of tumours that do not adequately respond to currently available immunotherapies.