On October 20, 2018 TESARO, Inc. (NASDAQ: TSRO), an oncology-focused biopharmaceutical company, today summarized updated Phase 1 GARNET data of TSR-042 (anti-PD-1 antibody) in patients with recurrent or advanced microsatellite instability high (MSI-H) endometrial cancer presented during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, TESARO, OCT 20, 2018, View Source [SID1234529996]). Blinded, pooled interim safety data from the Phase 3 PRIMA trial of niraparib in patients with first-line ovarian cancer regardless of biomarker status were also presented in a poster discussion session and additional data from the QUADRA trial of niraparib for treatment of late-line ovarian cancer beyond BRCAmut were presented in a poster display.

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"The updated results from GARNET presented at ESMO (Free ESMO Whitepaper) demonstrate robust clinical activity of TSR-042 in patients with MSI-H endometrial tumors," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "In addition, blinded, pooled interim safety data from the ongoing PRIMA study of niraparib as maintenance therapy in first line ovarian cancer demonstrated a favorable tolerability profile for niraparib when dosed according to a patient’s weight and platelet count compared to a fixed starting dose. These prospective data confirmed that adverse events are reduced for patients starting niraparib at an individualized dose, including a reduction in symptomatic events that are particularly meaningful to patients. We look forward to announcing top-line results for the PRIMA study in late 2019."

TSR-042 (anti-PD-1 antibody)

GARNET: Efficacy data indicates robust activity of TSR-042 in patients with MSI-high endometrial cancer
GARNET is a multicenter, open-label, Phase 1 dose-escalation study designed to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of TSR-042 in patients with advanced solid tumors. The weight-based dose escalation and fixed-dose safety portions of the GARNET study have been completed. The ongoing cohort expansion portion of GARNET is evaluating TSR-042 at a dose of 500 milligrams every 3 weeks (Q3W) for the first 4 cycles, and 1000 milligrams every 6 weeks (Q6W) thereafter in four cohorts: MSI-H endometrial cancer, MSI-H non-endometrial cancer, MSS endometrial cancer and non-small cell lung cancer (NSCLC). Data presented at ESMO (Free ESMO Whitepaper) included safety and efficacy data from the cohort of patients with MSI-H endometrial cancer.

At the time of data cutoff, 35 patients with MSI-H endometrial cancer had received treatment with TSR-042. Among the 25 patients with MSI-H endometrial cancer who had at least one post-baseline tumor assessment, one had a complete response and 12 had partial responses (including 1 unconfirmed response) by immune related RECIST (irRECIST) criteria (ORR 52%). Twelve of the 13 responses are ongoing (92%), including three patients with partial responses who have thus far received over 60 weeks of treatment with TSR-042. Three additional patients (12%) had stable disease. Median duration of response was not reached.

Preliminary safety findings among the 35 MSI-H endometrial patients indicate TSR-042 is generally well-tolerated. Grade ≥3 treatment-related treatment-emergent adverse events (TEAEs) were reported in 4 out of 35 patients (11.4%).

The data support the unique and convenient dose of TSR-042 of 500 mg Q3W for the first 4 doses, then 1000 mg Q6W thereafter. At this dose, TSR-042 maintained serum concentrations required to retain maximum receptor occupancy throughout the dosing cycle.

The GARNET study is intended to support a Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) in 2019.

ZEJULA (niraparib)

PRIMA: Prospective validation of individualized niraparib dose regimen based on patient baseline body weight & platelet counts; Rates of adverse events in blinded, pooled patient groups decreased with individualized starting dose compared to fixed starting dose
PRIMA is a double-blind, randomized Phase 3 study designed to evaluate niraparib versus placebo as maintenance therapy in first-line ovarian cancer patients. Platinum responsive patients were initially randomized 2:1 to start niraparib at 300 mg once-daily or placebo and the protocol was subsequently amended to require an individualized starting dose of 200 mg once-daily in patients with baseline weight <77kg or platelet count <150K/μL and 300 mg in all other patients. The trial remains blinded for efficacy and safety.

Among the 727 patients dosed on the study, 480 patients were treated with a fixed 300 mg starting dose of niraparib or placebo and 247 patients were treated with an individualized dose of 300 mg or 200 mg of niraparib based on weight and platelet count or placebo. The findings presented were from evaluable patients with ≥30 days of safety data from blinded pooled niraparib and placebo and indicate improved tolerability with niraparib at the individualized starting dose. TEAEs grade ≥ 3 were lower (36%) in the individualized dosing group (pooled niraparib and placebo) as compared with the group that received a fixed starting dose of 300 mg of niraparib or placebo (52.7%). There were fewer dose reductions and dose discontinuations in patients treated with the individualized starting dose compared with the fixed starting dose. TEAEs leading to treatment discontinuation remained low for both groups at 7.9% for the fixed starting dose and 5.3% for the individualized starting dose group.

The rates of hematologic toxicities of all grades, including grade ≥ 3, were lower with introduction of an individualized starting dose. Grade ≥3 non-hematologic toxicities (nausea, vomiting, fatigue, hypertension, and insomnia) decreased with an individualized starting dose.

QUADRA: Clinical benefit of niraparib treatment demonstrated in late-line ovarian cancer setting, including patients with platinum resistant and refractory disease
Late line ovarian cancer represents a high unmet medical need and efficacy of cytotoxic chemotherapy is limited in patients with heavily-pretreated ovarian cancer. Previous studies have shown meaningful activity of other PARP inhibitors in the late-line treatment of ovarian cancer only in populations with BRCA mutations. QUADRA, a single arm study, was conducted to assess the activity of ZEJULA monotherapy in the fourth-line or later treatment of patients with ovarian cancer, regardless of platinum sensitivity or biomarker status.

Niraparib treatment demonstrated durable clinical activity in late-line (≥ 4th line) patients with BRCAmut tumors, with an ORR of approximately 30%, including patients with platinum-sensitive, -resistant, and -refractory disease, and a median duration of response of 9.2 months. The clinical benefit rate (CBR; CR+PR+SD) at 16 weeks and 24 weeks were 56% and 38%, respectively. A gradient of clinical activity based on platinum sensitivity was demonstrated in the BRCAmut patient population, with greatest activity demonstrated in patients with platinum-sensitive disease (ORR 39%), mOS was not reached (95% CI 19, NE). However, even patients with platinum-resistant and platinum-refractory disease experienced benefit from niraparib treatment with ORR of 33% and 19%, and mOS of 26.0 and 23.3 months, respectively.

Clinical benefit of niraparib extended beyond patients with BRCA mutations in this late-line setting. Patients with non-BRCAmut/HRDpos platinum-sensitive disease had an ORR of 20%. In total, the biomarker-driven population (BRCAmut regardless of platinum status and non-BRCAmut HRDpos platinum-sensitive patients) included 98 patients with ORR of 26%, mDOR of 8.3 months, and a mOS of 23.3 months.

The safety profile in the QUADRA treatment study was consistent with the safety profile observed in the NOVA maintenance population.

Details of TESARO’s poster presentations are as follows (all times local):

ZEJULA (niraparib)

Saturday, October 20, 2018, 9:15 AM – 10:45 AM; Lecture time: 9:59 AM

A prospective evaluation of tolerability of niraparib dosing based upon baseline body weight (wt) and platelet (plt) count: Blinded pooled interim safety data from the PRIMA Study

Poster Discussion, Abstract: 941PD, Location: ICM – Room 13, Poster Displayed: Hall B4

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

QUADRA: A phase 2, open-label, single-arm study to evaluate niraparib in patients with relapsed ovarian cancer in 4th or later line of therapy: results from the BRCAmut subset

Poster Session, Abstract: 944P, Location: Hall A3

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

OVARIO: A single-arm, open-label phase 2 study of maintenance therapy with niraparib + bevacizumab in patients with advanced ovarian cancer after response to frontline platinum-based chemotherapy

Poster Session, Abstract: 999TiP, Location: Hall A3

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

Real world occurrence of top three clinical-trial reported adverse events of PARP inhibitor niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer, a national retrospective observational study of a 200 mg/day starting-dose cohort

Poster Session, Abstract: 986P, Location: Hall A3

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

Brain metastases in primary ovarian cancer: real-world data

Poster Session, Abstract: 946P, Location: Hall A3

TSR-042 (anti-PD-1)

Saturday, October 20, 2018, 9:15 AM – 10:45 AM; Lecture time: 9:15 AM

Preliminary safety, efficacy, and PK/PD characterization from GARNET, a phase 1 clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-H endometrial cancer

Poster Discussion, Abstract: 935PD, Location: ICM – Room 13, Poster displayed: Hall B4

Niraparib is marketed in the United States and Europe under trade name ZEJULA.

About ZEJULA (Niraparib)
ZEJULA (niraparib) is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated in the United States and in the EU for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. In preclinical studies, ZEJULA concentrates in the tumor relative to plasma, delivering greater than 90% durable inhibition of PARP 1/2 and a persistent antitumor effect. Important Safety Information Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including some fatal cases, was reported in 1.4% of patients receiving ZEJULA vs 1.1% of patients receiving placebo in Trial 1 (NOVA), and 0.9% of patients treated with ZEJULA in all clinical studies. The duration of ZEJULA treatment in patients prior to developing MDS/AML varied from <1 month to 2 years. All patients had received prior chemotherapy with platinum and some had also received other DNA damaging agents and radiotherapy. Discontinue ZEJULA if MDS/AML is confirmed.

Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients receiving ZEJULA. Grade ≥3 thrombocytopenia, anemia and neutropenia were reported in 29%, 25%, and 20% of patients receiving ZEJULA, respectively. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, in 3%, 1%, and 2% of patients, respectively. Do not start ZEJULA until patients have recovered from hematological toxicity caused by prior chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically thereafter. If hematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA, and refer the patient to a hematologist for further investigations.

Hypertension and hypertensive crisis have been reported in patients receiving ZEJULA. Grade 3-4 hypertension occurred in 9% of patients receiving ZEJULA vs 2% of patients receiving placebo in Trial 1, with discontinuation occurring in <1% of patients.
ZEJULA can cause fetal harm and females of reproductive potential should use effective contraception.

In clinical studies, the most common adverse reactions (Grades 1-4) in ≥10% of patients included: thrombocytopenia (61%), anemia (50%), neutropenia (30%), leukopenia (17%), palpitations (10%), nausea (74%), constipation (40%), vomiting (34%), abdominal pain/distention (33%), mucositis/stomatitis (20%), diarrhea (20%), dyspepsia (18%), dry mouth (10%), fatigue/asthenia (57%), decreased appetite (25%), urinary tract infection (13%), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation (10%), myalgia (19%), back pain (18%), arthralgia (13%), headache (26%), dizziness (18%), dysgeusia (10%), insomnia (27%), anxiety (11%), nasopharyngitis (23%), dyspnea (20%), cough (16%), rash (21%) and hypertension (20%).

Common lab abnormalities (Grades 1-4) in ≥25% of patients included: decrease in hemoglobin (85%), decrease in platelet count (72%), decrease in white blood cell count (66%), decrease in absolute neutrophil count (53%), increase in AST (36%) and increase in ALT (28%). Please see full U.S. prescribing information, including additional important safety information, available at www.zejula.com.

About GARNET
The ongoing Phase I GARNET trial is evaluating TSR-042 as monotherapy in patients with advanced solid tumors. GARNET included a weight-based dose escalation study (Part 1) and a fixed-dose safety study (Part 2A), both of which have been completed. Results of these studies were used to determine the recommended Phase 2 dose (RP2D; 500 mg Q3W for the first 4 cycles then 1000 mg Q6W). The study is now enrolling patients with MSI-H endometrial cancer, MSI-H non-endometrial cancer, MSS endometrial cancer, and NSCLC into four large expansion cohorts.

About TSR-042

TSR-042 is an investigational humanized anti-programmed death (PD)-1 monoclonal antibody that binds with high affinity to the PD-1 receptor and effectively blocks its interaction with the ligands PD-L1 and PD-L2. TSR-042 is the only anti-PD-1 therapy administered as monotherapy every 3 weeks for 4 doses then every 6 weeks thereafter. TSR-042 was developed as part of the collaboration between TESARO and AnaptysBio, Inc. This collaboration was initiated in March of 2014, and is focused on the development of monospecific antibody drugs targeting PD-1, TIM-3 (TSR-022), and LAG-3 (TSR-033), in addition to a bi-specific antibody drug candidate targeting PD-1/LAG-3 (TSR-075).

On October 20, 2018 Pfizer Inc.(NYSE:PFE) reported detailed overall survival (OS) data from the PALOMA-3 trial, which evaluated IBRANCE (palbociclib) in combination with fulvestrant compared to placebo plus fulvestrant in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer whose disease progressed on or after prior endocrine therapy (Press release, Pfizer, OCT 20, 2018, View Source [SID1234530013]). In the study, there was a numerical improvement in OS of nearly seven months with IBRANCE plus fulvestrant compared to placebo plus fulvestrant, although this difference did not reach the prespecified threshold for statistical significance (median OS: 34.9 months [95% CI: 28.8, 40.0] versus 28.0 months [95% CI: 23.6, 34.6]; HR=0.81 [95% CI: 0.64, 1.03], 1-sided p=0.0429). These data will be presented as a late-breaking oral abstract during the Presidential Symposium at the ESMO (Free ESMO Whitepaper) 2018 Congress (European Society for Medical Oncology) in Munich, Germany, and simultaneously published in The New England Journal of Medicine.

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The difference in median OS demonstrated in this analysis (6.9 months) is consistent with the improvement previously demonstrated for the primary endpoint of median progression-free survival (mPFS). In the updated PFS analysis for this study (non-prespecified), the combination of IBRANCE plus fulvestrant showed a statistically significant and clinically meaningful 6.6-month mPFS improvement compared to placebo plus fulvestrant (11.2 vs. 4.6 months; HR=0.50 [95% CI: 0.40-0.62], p<0.000001).1 Overall survival is a secondary endpoint of PALOMA-3, and the trial design was not optimized to detect a statistically significant difference in OS.

"It’s noteworthy that the magnitude of progression-free survival benefit observed in PALOMA-3 has translated to a similar difference of nearly seven months in overall survival, which is clinically meaningful. This is particularly significant given the challenges of demonstrating overall survival in this disease setting, where post-progression therapy is often substantially longer than time on study," said Massimo Cristofanilli, M.D., associate director for Translational Research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, as well as senior investigator of the PALOMA-3 trial. "The overall survival data, coupled with the previously demonstrated progression-free survival benefit, are encouraging for patients."

At the time of this analysis, follow-up was 44.8 months and approximately 60 percent (n=310) of events had occurred in the 521 patients enrolled. Patients on both arms received up to 10 lines (range 1-10) of post-progression treatment.

The trend toward OS favoring the IBRANCE plus fulvestrant arm was observed across most subgroups, with hazard ratios consistent with the overall population. In addition, for the overall population, the difference in OS was associated with prolonged time from randomization to first use of chemotherapy post-progression, an exploratory endpoint (HR=0.58 [95% CI: 0.47, 0.73], 1-sided p<0.000001). Median time to chemotherapy was 17.6 months (95% CI: 15.2, 19.7) for patients who received IBRANCE plus fulvestrant, twice that observed in patients who received placebo plus fulvestrant (8.8 months [95% CI: 7.3, 12.7]).

"Delaying the need for chemotherapy is a central goal of treatment for women with this disease. These new data from PALOMA-3 show that adding IBRANCE to fulvestrant led to a substantial improvement in this important area," said Nicholas Turner, M.D., Ph.D., professor of molecular oncology at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden NHS Foundation Trust, as well as principal investigator of the PALOMA-3 trial. "The difference in overall survival and prolonged time to chemotherapy demonstrated in PALOMA-3 further support the role of IBRANCE in combination with endocrine therapy as a standard of care in HR+, HER2- metastatic breast cancer."

"Looking at the data from the PALOMA-3 trial and across the PALOMA program, IBRANCE has transformed the treatment landscape for this disease," said Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development. "We are proud of the compelling body of evidence supporting the use of IBRANCE in this setting, and the difference this medicine continues to make in the lives of patients."

The most common adverse reactions in PALOMA-3 included neutropenia, leukopenia, infections, fatigue and nausea. No new safety signals observed with longer follow-up were identified as part of this final OS analysis.

About IBRANCE (palbociclib) 125 mg capsules

IBRANCE is an oral inhibitor of CDKs 4 and 6,2 which are key regulators of the cell cycle that trigger cellular progression.3,4 In the U.S., IBRANCE is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy.

IBRANCE currently is approved in more than 85 countries and has been prescribed to more than 160,000 patients globally.

The full prescribing information for IBRANCE can be found at www.pfizer.com.

IMPORTANT IBRANCE (palbociclib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Neutropenia was the most frequently reported adverse reaction in PALOMA-2 (80%) and PALOMA-3 (83%). In PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 15 of first 2 cycles and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (80% vs 6%), infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis (30% vs 14%), diarrhea (26% vs 19%), anemia (24% vs 9%), rash (18% vs 12%), asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting (16% vs 17%), decreased appetite (15% vs 9%), dry skin (12% vs 6%), pyrexia (12% vs 9%), and dysgeusia (10% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and anemia (5% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were decreased WBC (97% vs 25%), decreased neutrophils (95% vs 20%), anemia (78% vs 42%), decreased platelets (63% vs 14%), increased aspartate aminotransferase (52% vs 34%), and increased alanine aminotransferase (43% vs 30%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (66% vs 1%) and leukopenia (31% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), decreased platelets (62% vs 10%), increased aspartate aminotransferase (43% vs 48%), and increased alanine aminotransferase (36% vs 34%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg. The pharmacokinetics of IBRANCE have not been studied in patients requiring hemodialysis.

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