On October 20, 2018 Dynavax Technologies Corporation (NASDAQ:DVAX) reported interim data from its ongoing Phase 1b/2 SYNERGY-001 study investigating SD-101, Dynavax’s intratumoral TLR9 agonist, in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 therapy developed by Merck (known as MSD outside the United States and Canada) in patients with advanced melanoma naïve to anti-PD-1/L1 therapy (Press release, Dynavax Technologies, OCT 20, 2018, View Source [SID1234530110]). These data were presented in a late breaking poster and discussion session today at the ESMO (Free ESMO Whitepaper) 2018 Congress, in Munich, Germany.

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The company reported results on a total of 87 patients (Intention to Treat population) comparing two different doses of SD-101. In the study, 47 patients received ≤2mg of SD-101 in 1-4 lesions and 40 patients received 8 mg in a single lesion. The primary endpoints of this dose-expansion/dose-finding study are safety and preliminary efficacy. The results showed a 70% overall response rate (ORR) in advanced melanoma patients naïve to anti-PD-1/L1 therapy who received the ≤ 2 mg dose of SD-101 and a 48% ORR in the group receiving the 8 mg dose of SD-101. The combination of SD-101 and KEYTRUDA remains well tolerated with adverse events related to SD-101 being transient, mild to moderate flu-like symptoms.

"These results are encouraging because the overall response rate in the 2 mg group has remained consistent with the data presented at the 2018 American Society for Clinical Oncology annual meeting, even though the number of patients increased by more than 50 percent. In addition, median progression-free survival has not yet been reached, but statistically is expected to be at least 15.2 months, providing further validation of the potential benefit of the combination therapy," said Rob Janssen, M.D., Chief Medical Officer. "These data underscore the value of stimulating the innate immune response through TLR9 and build on clinical evidence around the proposed mechanism of action for SD-101."

Highlights from the poster presentation (LBA45)

ORR of 70% (33 of 47), for advanced melanoma patients who received the ≤ 2 mg dose of SD-101 per lesion
Durable response in patients who received ≤ 2 mg dose of SD-101 with 85% 6-month progression-free survival (PFS) rate
Median PFS not reached in patients who received ≤ 2 mg dose of SD-101 with a lower bound of the 95% confidence interval suggesting a minimum ongoing PFS of 15.2 months
Observed responses in injected lesion(s) and non-injected distant lesions, including visceral metastases in the liver and lung
Response rates appeared similar regardless of PD-L-1 status
AEs related to SD-101 treatment were transient, mild to moderate flu-like symptoms at both the ≤ 2mg and the 8 mg dosing levels
No increase in the frequency of immune-related adverse events over individual monotherapies reported in other studies1,2 nor evidence of any new safety signals
Dynavax Conference Call and Webcast
Dynavax will host a conference call and webcast on Sunday at 1:00pm EDT (7:00 PM CEST). The live webcast can be accessed in the "Investors and Media" section of the company’s website at www.dynavax.com. The conference call can be accessed by dialing (866) 420-4066 in the U.S. or (409) 217-8237 internationally, using the conference ID 2036717. A replay of the webcast will be available following the live event.

About SYNERGY-001 (KEYNOTE-184)
SYNERGY-001, previously referred to as MEL-01, is the dose-escalation and expansion study of SD-101 in combination with KEYTRUDA which includes patients with histologically or cytologically confirmed unresectable Stage IIIC/IV melanoma. The primary endpoints of the trial are safety and preliminary efficacy of intratumoral SD-101 in combination with KEYTRUDA.

On October 20, 2018 Novartis reported positive results from the global Phase III SOLAR-1 trial evaluating the investigational alpha-specific PI3K inhibitor BYL719 (alpelisib) in combination with fulvestrant (Press release, Novartis, OCT 20, 2018, View Source [SID1234529998]). The trial evaluated the efficacy and safety of alpelisib in postmenopausal women with PIK3CA mutated hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer that progressed on or after an aromatase inhibitor with or without a CDK4/6 inhibitor. These data will be presented today at the official press briefing at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress and as a late-breaker during the Presidential Symposium (Abstract LBA3_PR).

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In patients with PIK3CA mutated HR+/HER2- advanced breast cancer, BYL719 plus fulvestrant demonstrated a median progression-free survival (PFS) of 11 months (95% CI: 7.5-14.5 months) compared to 5.7 months (95% CI: 3.7-7.4 months) for fulvestrant alone. BYL719 plus fulvestrant reduced the risk of death or progression in those patients by an estimated 35% compared to fulvestrant alone (HR=0.65; 95% CI: 0.50-0.85; p<0.001). Overall response rate (ORR), indicating a reduction in tumor size of at least 30%, was more than doubled in patients with measurable disease who received BYL719 plus fulvestrant (36%) compared to those receiving fulvestrant alone (16%)[1].

"The results from SOLAR-1 are the most encouraging observed to date from a trial evaluating a PI3K inhibitor for patients with PIK3CA mutated HR+/HER2- advanced breast cancer," said Fabrice André, MD, PhD, research director and head of INSERM Unit U981, and professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France. "These data have the potential to allow physicians to address an unmet need in this patient population by using a biomarker-driven treatment to inform their sequencing decisions."

PFS treatment effect was consistent across all subgroups, and regardless of whether aromatase inhibitor treatment was given, with or without a CDK4/6 inhibitor. The significant PFS improvement demonstrated with BYL719 plus fulvestrant in patients with a PIK3CA mutation was not observed for patients without the mutation[1].

"We are excited about the meaningful results seen in SOLAR-1 and about the possibility to reimagine what potential treatment options could look like for patients living with PIK3CA mutated HR+/HER2- advanced breast cancer – some of who were previously treated with a CDK4/6 inhibitor," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "We are actively engaging in discussions on these results with health authorities worldwide."

Most adverse events were mild to moderate in severity and generally manageable through dose modifications and medical management. The discontinuation rate of BYL719 plus fulvestrant due to adverse events was 5% compared to 1% for fulvestrant alone. The most common all-grade adverse events (>=30%) were hyperglycemia (64% vs 10%), diarrhea (58% vs. 16%), nausea (45% vs. 22%), decreased appetite (36% vs. 11%) and rash (36% vs. 6%). Of these, the most common grade 3/4 events (>=5%) were hyperglycemia (37% vs. <1%), rash (10% vs. <1%), and diarrhea (7% vs. <1%)[1].

The SOLAR-1 trial is ongoing to evaluate secondary endpoints, including overall survival. Further analysis from SOLAR-1 will be presented and discussed at future medical congresses.

About PI3K inhibition in advanced breast cancer
Studies have established the role of PI3K signaling in several processes for cancer progression, including cell metabolism, growth, survival and motility[3]. Activation of the PI3K pathway in breast cancer is associated with resistance to endocrine therapy, disease progression and poorer prognosis[4],[5].

Proteins in the PI3K pathway consist of four smaller parts called isoforms[6]. Approximately 40% of HR+ advanced breast cancer patients have genetic mutations that activate the alpha isoform, called PIK3CA mutations[2]. Mutations in the three other isoforms are typically not associated with advanced breast cancer[6].

Currently, there are no approved PI3K inhibitors for breast cancer.

About SOLAR-1
SOLAR-1 is a global, Phase III randomized, double-blind, placebo-controlled trial studying investigational BYL719 in combination with fulvestrant for postmenopausal women with PIK3CA-mutated HR+/HER2- advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor[1].

The trial randomized 572 patients. Patients were allocated based on tumor tissue assessment to either a PIK3CA-mutated cohort or a PIK3CA non-mutated cohort. Within each cohort, patients were randomized in a 1:1 ratio to receive continuous oral treatment with BYL719 (300mg once daily) plus fulvestrant (500 mg every 28 days + Cycle 1 Day 15) or placebo plus fulvestrant. Stratification was based on visceral metastases and prior CDK4/6 inhibitor treatment[1].

The primary endpoint is local investigator assessed PFS using RECIST 1.1 for patients with the PIK3CA mutation. Secondary endpoints include but are not limited to overall survival, overall response rate, clinical benefit rate, health-related quality of life, efficacy in PIK3CA non-mutated cohort, safety and tolerability[1].

About BYL719 (alpelisib)
BYL719 is an investigational, orally bioavailable, alpha-specific PI3K inhibitor. In breast cancer cell lines harboring PIK3CA mutations, BYL719 has been shown to potentially inhibit the PI3K pathway and have antiproliferative effects. In addition, cancer cell lines with PIK3CA mutations were more sensitive to BYL719 than those without the mutation across a broad range of different cancers[7].

On October 20, 2018 OncoMed Pharmaceuticals, Inc. (NASDAQ:OMED), a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer therapeutics, reported interim results from its ongoing Phase 1b trial investigating navicixizumab, OncoMed’s anti-DLL4/VEGF bispecific antibody, in combination with paclitaxel in patients with platinum-resistant ovarian cancer (Press release, OncoMed, OCT 20, 2018, View Source [SID1234530049]).

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The interim results were presented at the European Society for Medical Oncology in Munich. The patients had received a median of four prior therapies, all of whom had received prior paclitaxel and 69% had received prior bevacizumab. Twenty-two of the 26 patients (85%) treated with the novel regimen experienced clinical benefit. Notably 11 of the 26 patients (42%) achieved a partial response and the median progression-free survival was 5.4 months (95% CI: 3.5-8.0 months). Historical response rates for patients with heavily pretreated platinum-resistant ovarian cancer treated with chemotherapy are typically 15% or less.

"These are impressive results that warrant further evaluation in this historically difficult-to-treat patient population," said Kathleen Moore, M.D., Jim and Christy Everest Endowed Chair in Cancer Research, Clinical Research Director, University of Oklahoma Health Science Center and one of the lead investigators for the Phase 1b clinical trial. "When ovarian cancer stops responding to platinum-based therapy, our best option is chemotherapy plus bevacizumab, which may be effective, but often for only a short duration. Following this line of therapy, there are no approved, effective options for patients. Combination weekly paclitaxel and navicixizumab appears to provide durable responses among patients with multiple lines of prior therapy and/or prior exposure to bevacizumab, which represents a high unmet need."

The ongoing Phase 1b multicenter, open-label, dose-escalation and expansion trial is designed to assess the safety, preliminary efficacy, immunogenicity, pharmacokinetics and biomarker effects of navicixizumab plus paclitaxel. The trial has been expanded to enroll up to 60 patients with platinum-resistant ovarian cancer (including fallopian tube or primary peritoneal cancers) who have previously received bevacizumab and/or have failed at least two prior therapies.

Additional highlights from the poster were:

The median number of prior therapies was four. All patients had previously received paclitaxel and 69% had received bevacizumab.
The RECIST response rate was 42% and the RECIST response rate in the bevacizumab naïve and bevacizumab pretreated patients was 57% and 33%, respectively.
CA-125 is a widely utilized tumor marker for ovarian cancer that is used along with radiographic assessments to determine the efficacy outcome to treatment. Of the 23 patients evaluable for a GCIG CA-125, 14 (61%) had a response. Specifically, the CA-125 response rates in the bevacizumab naïve and bevacizumab pretreated patients were 100% and 47%, respectively.
The overall median progression free survival (PFS) was 5.4 months (95% CI: 3.5 — 8 months). The median PFS for the subset of bevacizumab pretreated patients was 3.7 months (95% CI: 3.3 months — not reached).
The most common related adverse events of any grade related to navicixizumab were hypertension (53%), fatigue (32%), diarrhea (24%) and headache (18%). Other related rare adverse events of special interest were one Grade 2 pulmonary hypertension, one Grade 1 related heart failure, one Grade 4 related gastrointestinal perforation and one Grade 4 thrombocytopenia. Three patients (12%) experienced infusion reactions that were associated with anti-drug antibodies which impacted drug exposure.
About Navicixizumab
OncoMed’s anti-DLL4/VEGF bispecific antibody, navicixizumab, is designed to inhibit the function of both DLL4 and VEGF and thereby induce potent anti-tumor responses while mitigating certain angiogenic-related toxicities. Navicixizumab was developed utilizing OncoMed’s BiMAb bispecific platform technology, which enables the design of bispecific antibodies comparable to traditional monoclonal antibodies but possessing dual target-binding specificity. In preclinical studies, navicixizumab demonstrated robust in vivo anti-tumor efficacy across a range of solid tumor xenografts, including colon, ovarian, lung and pancreatic cancers, among others. Further, in preclinical studies dual inhibition of DLL4 and VEGF appeared to exhibit synergistic anti-tumor activity at doses where blockade of either target alone elicited sub-optimal activity. In a Phase 1a study with single-agent navicixizumab published in Investigational New Drugs, 19 of 66 patients with various types of refractory solid tumors had tumor shrinkage following treatment with navicixizumab. Notably, 3 of the 12 (25%) ovarian cancer patients treated in the trial achieved a partial response with single-agent navicixizumab therapy

On October 20, 2018 BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX) (TASE: BLRX.TA), a clinical-stage biopharmaceutical company focused on oncology and immunology, reported its additional data from the in-depth analyses of biopsies of the dual combination arm of the Phase 2a COMBAT/KEYNOTE-202 study, evaluating patients with metastatic pancreatic adenocarcinoma (PDAC) treated with BL-8040 in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 therapy marketed by Merck & Co., Inc., Kenilworth, N.J., USA (known as MSD outside of the United States and Canada) (Press release, BioLineRx, OCT 20, 2018, View Source;p=RssLanding&cat=news&id=2372552 [SID1234530001]). The results presented today at a poster discussion session at the European Society for Medical Oncology 2018 Congress, in Munich, Germany, demonstrate that BL-8040 significantly improves T-cell infiltration into the tumor and reduces immunosuppression in the tumor microenvironment. These data follow top-line results of the COMBAT/KEYNOTE-202 study announced yesterday, October 19, 2018, showing encouraging disease control and extended overall survival, particularly in patients undergoing second-line treatment.

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The study included 37 patients with metastatic PDAC who had disease progression after one or more previous lines of treatment. Study treatment consisted of an initial 5-day priming period of BL-8040 monotherapy, followed by repeated 3-week cycles of BL-8040 in combination with KEYTRUDA. In addition to clinical efficacy assessments, the study included a number of pharmacodynamic assessments to support BL-8040’s mechanism of action as an immuno-oncology agent.

The additional data from in-depth analyses of biopsies taken at screening and following monotherapy or combination treatment of BL-8040 and KEYTRUDA demonstrate that in 75% of the available biopsies, BL-8040 treatment promotes an increase in the number of infiltrating CD4+, CD8+ and CD8+Granzyme B+ cytotoxic T-cells. The greatest improvement in T-cell infiltration was observed following combination treatment of BL-8040 and KEYTRUDA and was correlated with stable disease for 8 cycles of treatment. Furthermore, increased infiltration of activated CD4 and CD8 T-cells was accompanied by a pronounced decrease in the number of tumor cells, as well as by a decrease in myeloid-derived suppressor cells, a cell type known to impede the anti-tumor immune response.

Philip Serlin, Chief Executive Officer of BioLineRx, commented. "The data we disclosed today further support BL-8040 as a powerful immune modulating agent, which promotes infiltration of T-cells into the tumor and decreases immuno-suppressive cells in the tumor microenvironment, even more so when combined with KEYTRUDA. This, once again, attests to the potential of the combination treatment as an effective immunotherapy for pancreatic cancer. We look forward to commencing the triple combination arm through the addition of chemotherapy expected by the end of this year, with results expected in the second half of 2019."

About the COMBAT/KEYNOTE-202 Study

The Phase 2a COMBAT/KEYNOTE-202 study is currently an open-label, multicenter, single-arm trial designed to evaluate the safety and efficacy of the combination of BL-8040 and KEYTRUDA (pembrolizumab), an anti-PD-1 therapy marketed by Merck & Co., Inc., Kenilworth, N.J., USA (known as MSD outside the United States and Canada), in over 30 subjects with metastatic pancreatic adenocarcinoma. The study is primarily designed to evaluate the clinical response, safety and tolerability of the combination of these therapies, and is being carried out in the US, Israel and additional territories. The study is being conducted by BioLineRx under a collaboration agreement signed in 2016 between BioLineRx and MSD, through a subsidiary, to support a Phase 2a program investigating BioLineRx’s BL-8040 in combination with KEYTRUDA in patients with metastatic pancreatic cancer.

In July 2018, the Company announced the expansion of its immuno-oncology collaboration with MSD to include a triple combination arm investigating the safety, tolerability and efficacy of BL-8040, KEYTRUDA and chemotherapy. The triple combination arm will focus on second-line pancreatic cancer patients. Thirty to fifty patients will be enrolled in this arm, planned for initiation in the fourth quarter of 2018.

BL-8040, BioLineRx’s lead oncology platform, is a CXCR4 antagonist that has been shown in several clinical trials to be a robust mobilizer of immune cells to peripheral blood and to be effective at inducing direct tumor cell death. In addition, clinical findings have demonstrated the ability of BL-8040 to mediate infiltration of T-cells into tumors that were previously immunologically "cold" and devoid of immune cell infiltrate. Immune checkpoint inhibitors (such as KEYTRUDA) produce anti-cancer effects by increasing the activity of T-cells through blockade of the interaction between the immune checkpoint receptor PD-1, on T-cells, and its ligand PD-L1, on tumor cells. Pancreatic cancers have very little T-cell infiltrate, making them less susceptive to checkpoint blockade than other tumors that are infiltrated by T-cells. Therefore, combining BL-8040 with immune checkpoint blockade is predicted to increase the responsiveness of pancreatic cancer patients to immunotherapy. Further increase in the sensitivity of pancreatic cancer cells to BL-8040 and KEYTRUDA may be achieved by chemotherapy-mediated immunogenic cell death and exposure of new tumor antigens, resulting in activation of new anti-cancer T cell clones.

About BL-8040

BL-8040 is a short synthetic peptide for the treatment of hematological malignancies, solid tumors, and stem cell mobilization. It functions as a high-affinity best-in-class antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a number of clinical and pre-clinical studies, BL-8040 has shown robust mobilization of cancer cells and immune-cells, sensitization of cancer cells to chemo- and bio-based anti-cancer therapies, and direct anti-cancer effect by inducing programmed cell death (apoptosis). BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.

On October 20, 2018 Agenus Inc. (NASDAQ: AGEN), an immuno-oncology company with a pipeline of immune checkpoint antibodies, cancer vaccines, and adoptive cell therapies2, reported its clinical data on its lead CTLA-4 and PD-1 programs today at the 2018 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, in Munich, Germany (Press release, Agenus, OCT 20, 2018, View Source;ctla-4-at-esmo-2018-300734715.html [SID1234530018]).

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"We have initiated expanded clinical trials designed for potential approval of our proprietary PD-1 and CTLA-4 antibodies in second line cervical cancer," said Garo Armen, Ph.D., Chairman and CEO of Agenus. "We are pursuing both monotherapy and combination trials as a dual track regulatory strategy with a planned BLA filing as early as 2020."

Data presented at ESMO (Free ESMO Whitepaper) is based on 76 patients treated with PD-1 (AGEN2034) as well as combination PD-1 and CTLA-4 (AGEN1884) regimens.

Agenus’ anti-PD-1 (AGEN2034) and CTLA-4 (AGEN1884) reveal clinical activity across multiple solid tumors, including breast and gynecologic cancers such as cervical and ovarian.
Patients treated with AGEN2034 reveal a clinical benefit rate of 68% in evaluable patients with metastatic and/or locally advanced solid tumors, and in 3 of 7 evaluable patients with refractory cervical cancer.
Data from combination AGEN2034 plus AGEN1884 show similar trends; early clinical benefit observed in 7 of 16 evaluable patients with ovarian, breast, and soft tissue sarcoma, including a durable response in a patient with ovarian cancer.
Since the ESMO (Free ESMO Whitepaper) data cut-off, early evidence of clinical benefit was observed in patients with cervical cancer treated with combination AGEN2034 and AGEN1884. ESMO (Free ESMO Whitepaper) posters are available at View Source

1Clinical benefit is defined as complete response, partial response and/or disease stabilization
2Through AgenTus Therapeutics, a subsidiary of Agenus