On June 4, 2018 Molecular Templates, Inc. (Nasdaq:MTEM), a clinical stage biopharmaceutical company focused on the discovery and development of Engineered Toxin Bodies, a new class of targeted biologic therapies that possess unique mechanisms of action in oncology, reported that data on two of its pipeline programs were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2018, held June 1-5 in Chicago, Illinois (Press release, Molecular Templates, JUN 4, 2018, View Source [SID1234527147]).

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MT-3724

Poster Title: Safety and Efficacy of Anti-CD20 Immunotoxin MT-3724 in Relapsed/Refractory B-cell non-Hodgkin Lymphoma (NHL) in a Phase 1 Study
First Author: Paul A. Hamlin, MD, Memorial Sloan Kettering Cancer Center
The poster summarized interim results from a Phase I and Phase Ib extension study of B-cell non-Hodgkin’s lymphoma (NHL) patients treated with MT-3724 who had previously relapsed after anti-CD20 Mab and chemotherapy. Consistent with the mechanism of action, enzymatic ribosome inactivation, the best activity is observed in heavily pretreated patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (N=18; median of five prior therapies).

Patients with high circulating levels of rituximab (RTX) at study entry showed poor response to MT-3724 due to competitive inhibition and blocking of CD20 receptor by RTX. As a result, the ongoing Phase Ib extension and future studies of MT-3724 will enroll only patients with low levels of RTX.

The preliminary objective response rate in DLBCL patients with low serum Rituxan levels at study entry (N=10) was 30%, with a disease control rate of 70%, including two stable disease patients that had tumor reductions of 47% and 49%. The ongoing Phase Ib study will further characterize the response rate and duration of response.

MT-3724 was generally well tolerated and a redefined maximum tolerated dose (MTD) of 50 mcg/kg with a maximum of 6 mg per dose was implemented based on experience with patients with high body weight who received a high total dose at 75mcg/kg. Enrollment in the study has recently resumed after approval of the new MTD.

In addition to this ongoing Phase Ib extension, Molecular Templates expects to start Phase II combinations studies in 2H18 and a Phase II monotherapy study at the end of the year that may be pivotal.

Evofosfamide

Poster Title: Unexpected Pharmacokinetics of Evofosfamide Observed in Phase III MAESTRO Study
First Author: Jack P. Higgins, Ph.D., Molecular Templates, Inc.
This poster compares the pharmacokinetic (PK) profile of evofosfamide from the Phase II ("404" study) and Phase III ("MAESTRO") trials completed in patients with advanced pancreatic cancer. The Phase II ("404") study of evofosfamide in pancreatic cancer (N=214) showed promising response rates, progression-free survival, and overall survival. MAESTRO, a Phase III study in the same patient population (N=693) failed to replicate the clinical benefit seen in the Phase II ("404") study. A new ethanol-based formation was introduced before the initiation of MAESTRO and the drug exposure was substantially lower than the exposure in the Phase II ("404") study at the same dose. In the Japanese MAESTRO patients who received evofosfamide (N=59), substantially higher drug exposure was observed with correspondingly better clinical outcomes versus patients in the study from the rest of the world. We surmise that the formulation change may have adversely affected drug exposure and may have caused the reduced clinical benefit observed in MAESTRO.

Evofosfamide (in the current ethanol-based formulation) at higher doses is currently being evaluated in a Phase I study, in combination with ipilimumab, in an attempt to replicate the exposure seen with the previous formulation in Phase II ("404") study. Molecular Templates plans to explore potential partnership opportunities for further development of evofosfamide.

On June 4, 2018 Pierre Fabre and its partner Array BioPharma Inc. reported updated results from the Phase 3 COLUMBUS trial in BRAF-mutant advanced melanoma (Press release, Array BioPharma, JUN 4, 2018, View Source [SID1234527163]). The results showed median overall survival (mOS) was 33.6 months for patients treated with the combination of encorafenib and binimetinib compared with 16.9 months for patients treated with vemurafenib as a monotherapy. The combination reduced the risk of death compared with vemurafenib monotherapy (hazard ratio [HR] of 0.61 [95% CI: 0.47–0.79], p<0.0001]. The observed efficacy of vemurafenib in the control arm is also consistent with historical data, providing an additional benchmark for validating the patient population and results observed in COLUMBUS.1,2 Further, the two-year OS with the combination therapy was 58%. These results will be part of an oral presentation today at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting in Chicago, Illinois, and have been selected for the "Best of ASCO (Free ASCO Whitepaper)" program.

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"These data indicate that regardless of treatment group, the use of subsequent immunotherapies was similar, and therefore indicate that post-trial treatments are unlikely to have contributed to the OS results we’ve seen"

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Importantly, the presentation included data showing limited use of post-trial immunotherapy, which is consistent with other published pivotal trials of BRAF and MEK inhibitors in BRAF-mutant advanced melanoma.1,3

"These data indicate that regardless of treatment group, the use of subsequent immunotherapies was similar, and therefore indicate that post-trial treatments are unlikely to have contributed to the OS results we’ve seen," said Professor Reinhard Dummer, University of Zurich, lead author and Vice-Chairman of the Department of Dermatology in the University Hospital of Zürich, Switzerland. "We’re pleased to present this data at ASCO (Free ASCO Whitepaper) which builds upon previous analyses of the COLUMBUS data and further support our belief that encorafenib and binimetinib could be a promising new treatment option for patients with BRAF-mutant advanced melanoma."

Additionally, the updated median progression-free survival (mPFS) results for patients treated with the combination of encorafenib and binimetinib remained consistent with what was previously reported: 14.9 months versus 7.3 months for patients treated with vemurafenib (HR=0.51 [95% CI 0.39–0.67]; p<0.0001).

As previously reported, the combination of encorafenib and binimetinib was generally well-tolerated. Grade 3–4 adverse events (AEs) that occurred in more than 5% of patients receiving the combination were increased gamma-glutamyltransferase (GGT; 9%), increased blood creatine phosphokinase (CK; 7%) and hypertension (6%). The incidence of selected any grade AEs of special interest, defined based on toxicities commonly associated with commercially available BRAF+MEK inhibitor treatments, for patients receiving the combination of encorafenib and binimetinib included: rash (22%), serous retinopathy including retinal pigment epithelial detachment (20%), pyrexia (18%) and photosensitivity (5%). Full safety results of COLOMBUS Part 1 were published in The Lancet Oncology.

About Melanoma
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates.4,5 There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma.4,6,7,8

About COLUMBUS
The COLUMBUS trial (NCT01909453) is a two-part, international, randomized, open-label Phase 3 trial evaluating the efficacy and safety of the combination of encorafenib and binimetinib compared with vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation. Prior immunotherapy treatment was allowed. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the trial. Patients were randomized into two parts:

In Part 1, 577 patients were randomized 1:1:1 to receive encorafenib 450 mg daily + binimetinib 45 mg twice daily (COMBO450); encorafenib 300 mg daily (ENCO 300); or vemurafenib 960 mg twice daily as a monotherapy. The dose of encorafenib in the combination arm is 50% higher than the single-agent maximum tolerated dose of 300 mg. A higher dose of encorafenib was possible due to improved tolerability when combined with binimetinib. The primary endpoint for the COLUMBUS trial was a median progression-free survival (mPFS) comparison of the COMBO450 arm versus vemurafenib. mPFS is determined based on tumor assessment (RECIST version 1.1 criteria) by a Blinded Independent Central Review (BICR). Secondary endpoints include a comparison of the mPFS of COMBO450 arm to that of ENCO300 and a comparison of overall survival (OS) in patients treated in the COMBO450 arm to that of vemurafenib alone. Results from Part 1 of the COLUMBUS trial previously published in The Lancet Oncology earlier this year (online March 2018, print May 2018), showed that COMBO450 more than doubled mPFS in patients with advanced BRAF-mutant melanoma, with a mPFS of 14.9 months compared with 7.3 months observed with vemurafenib (HR 0.54 [95% CI 0.41-0.71], p<0.0001). In the secondary mPFS comparison of COMBO450 to ENCO300, ENCO300 demonstrated a mPFS of 9.6 months (HR 0.75 [95% CI 0.56-1.00], p=0.051).
In Part 2, 344 patients were randomized 3:1 to receive encorafenib 300 mg daily plus binimetinib 45 mg twice daily (COMBO300) or ENCO300. Part 2 was designed to provide additional data to help evaluate the contribution of binimetinib to the combination of encorafenib and binimetinib.
As the secondary endpoint comparison of mPFS between the COMBO450 arm and ENCO300 arm in Part 1 did not achieve statistical significance, the protocol-specified analysis of OS is descriptive.

About Encorafenib and Binimetinib
BRAF and MEK are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities, including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma and colorectal cancer. Encorafenib is a late-stage small molecule BRAF inhibitor and binimetinib is a late-stage small molecule MEK inhibitor, both of which target key enzymes in this pathway. Encorafenib and binimetinib are being studied in clinical trials in advanced cancer patients, including the Phase 3 COLUMBUS trial and the Phase 3 BEACON CRC trial.

Pierre Fabre has exclusive rights to commercialize encorafenib and binimetinib in Europe, Asia, Latin America and Australia. Pierre Fabre’s development partner, Array BioPharma, has exclusive rights in the U.S. and Canada, and has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea. Encorafenib and binimetinib are investigational medicines and are not currently approved in any country.

On June 4, 2018 Euronext Paris: FR0010331421 – IPH) reported updated preliminary clinical data from an ongoing Phase I dose escalation and expansion study evaluating the safety and efficacy of the combination of monalizumab, a first-in-class monoclonal antibody targeting NK and T cell checkpoint receptor NKG2A, with durvalumab in patients with recurrent/metastatic microsatellite-stable colorectal cancer (MSS-CRC) (Press release, Innate Pharma, JUN 4, 2018, View Source [SID1234527252]). This trial is being conducted by MedImmune, AstraZeneca’s global biologics research and development arm, through a co-development and commercialization agreement.

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In a poster presentation made at the Gastrointestinal (Colorectal) Cancer session on Sunday, June 3 2018, during the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), the combination of monalizumab and durvalumab showed encouraging anti-tumor activity in this difficult-to-treat patient subset.

"The preliminary data so far suggest that the combination of monalizumab and durvalumab may hold promise in some patients with MSS-CRC, a population historically unresponsive to PD-1/L1 therapy", said study investigator Neil H. Segal, MD., PhD., medical oncologist at Memorial Sloan Kettering Cancer Center, New York.

Pierre Dodion, Chief Medical Officer at Innate Pharma, added: "We are encouraged by the preliminary results from the ongoing trial observed in a heavily pretreated MSS-CRC patient population. These data have prompted our partner AstraZeneca/MedImmune to further expand the study with additional patient cohorts to explore the novel combination of this first-in-class antibody, monalizumab, with durvalumab on top of current standard of care therapies in patients with less heavily pretreated disease".

Key findings from the MSS-CRC expansion cohort:

Updated preliminary clinical data on the expansion cohort of microsatellite-stable colorectal cancer patients (MSS-CRC) presented at ASCO (Free ASCO Whitepaper) are based on the cut-off date of April 23, 2018. Forty patients are evaluable for safety and 39, for efficacy. Thirty five (88%) patients had 2 or more prior lines of therapy for recurrent/metastatic disease. Efficacy data show an overall response rate (ORR) of 8%, with confirmed partial response in 3 patients (8%) and stable disease (SD) in 11 patients (28%), including 3 SD patients with tumor reduction who continued therapy for >200 days. The median duration of response was 16.1 weeks at the cut-off date. Data demonstrated a disease control rate (DCR) of 31% at 16 weeks.

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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Two out of Five Drugs at ASCO (Free ASCO Whitepaper) 2018 are in Immuno-Oncology:

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

The 10 Most Reported-On Drug Targets from More than 300 at ASCO (Free ASCO Whitepaper) 2018:

There are close to 30 First-in-Class Drug Targets at ASCO (Free ASCO Whitepaper) 2018:

 

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On June 3, 2018 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that a poster titled "FIGHT: A Phase 3 Randomized, Double-Blind, Placebo Controlled Study Evaluating Bemarituzumab (FPA144) and Modified FOLFOX6 (mFOLFOX6) in Patients with Previously Untreated Advanced Gastric and Gastroesophageal Cancer with a Dose Finding Phase 1 Lead-In" was presented today at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Five Prime Therapeutics, JUN 3, 2018, View Source [SID1234527078]). The poster (Abstract #TPS4135), is available at View Source

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"Patients with advanced gastric or gastroesophageal junction cancer need new treatment options, particularly those whose tumors overexpress FGFR2b and whose prognosis is especially poor," said Helen Collins, M.D., senior vice president and chief medical officer of Five Prime. "We have seen encouraging monotherapy activity with FPA144 as a late-line treatment for gastric cancer and we believe that combining with chemotherapy in the front-line setting will provide the greatest patient benefit. Our global Phase 1/3 FIGHT trial is studying bemarituzumab in combination with mFOLFOX6 in patients with newly diagnosed gastric and gastroesophageal junction cancer whose tumors overexpress FGFR2b with the goal of providing a new treatment option for patients."

FIGHT Trial

In December 2017, Five Prime initiated the Phase 1 portion (NCT03343301) of the Phase 1/3 FIGHT (FGFR2b Inhibition in Gastric and Gastroesophageal Junction Cancer Treatment) global registrational trial. The Phase 1 safety lead-in portion of the trial is designed to identify a recommended dose of bemarituzumab in combination with the modified FOLFOX6 standard-of-care chemotherapy regimen (mFOLFOX6) to support the initiation of the Phase 3 portion of the trial.

The Phase 3 portion of the FIGHT trial will evaluate bemarituzumab in combination with mFOLFOX6 versus placebo plus mFOLFOX6 in approximately 550 patients with gastric cancer (GC) or gastroesophageal junction (GEJ) cancer whose tumors overexpress FGFR2b. The Phase 3 portion of the trial is expected to begin in the second half of 2018 and will include more than 250 sites in the U.S., Europe and Asia, including China, South Korea and Japan, where the incidence of gastric cancer is high.

The primary endpoint of the FIGHT trial is overall survival (OS) with secondary endpoints of progression-free survival (PFS), objective response rate (ORR), safety and pharmacokinetic (PK) parameters.

Previous Bemarituzumab Trial Results

Data from a Phase 1 clinical trial of single-agent bemarituzumab were presented at the 2017 ASCO (Free ASCO Whitepaper) Annual Meeting. Bemarituzumab demonstrated single-agent activity and an acceptable safety profile in heavily pretreated patients with metastatic gastric cancer whose tumors overexpress FGFR2b.

Efficacy:

In 21 treated patients with late-line GC/GEJ and high FGFR2b overexpression:
ORR was 19.0% with 4 confirmed PRs
Disease control rate was 54.9%
Median duration of response was 15.4 weeks
Overall safety:

Bemarituzumab was well tolerated
There were no dose-limiting toxicities
Maximum tolerated dose was not reached during dose escalation
Unmet Need in GC and GEJ

GC, including GEJ cancer, is the fifth most common cancer worldwide and third leading cause of cancer death. More than 50 percent of GC cases occur in eastern Asia.

Current first-line chemotherapy treatments prolong survival by approximately 6 months compared to best supportive care but median OS remains poor with literature-reported ranges of approximately 10 to 11 months and PFS from 5 to 5.6 months. An unmet medical need exists in the treatment for GC/GEJ since few treatment options following progression are available after first-line chemotherapy.

The presence of FGFR2 amplification or FGFR2b overexpression is associated with a worse prognosis and is present in approximately 10% of patients with GC/GEJ.

FGFs can stimulate transformation and proliferation of tumor cells through signaling mediated by FGF receptors (FGFR 1-4). FGFR2 has 2 splice variants (b and c).

FGFR2b is expressed in tissues of epithelial origin and alterations in FGF/FGFR2 pathway are associated with gastric, breast and other cancers. As a result, targeting this pathway appears to be important in GC/GEJ cancer treatment.

Rationale for Combination with Chemotherapy and Companion Diagnostics

Five Prime made a strategic decision to pursue a front-line bemarituzumab plus chemotherapy combination trial based on preclinical data that showed additive efficacy of bemarituzumab plus chemotherapy. Mutational heterogeneity of GC/GEJ suggests that combining bemarituzumab plus chemotherapy will result in improved activity by acting on non-FGFR2b overexpressing tumor cells and by improving the activity of bemarituzumab in FGFR2b overexpressing tumor cells.

Five Prime is developing companion diagnostics to identify FGFR2b overexpression using an IHC test and FGFR2 gene amplification using ctDNA analysis. Five Prime will use both assays to select patients for the FIGHT trial to identify the estimated 10% of patients with gastric and GEJ tumors that would qualify for the trial.

About Bemarituzumab

Bemarituzumab is a first-in-class, isoform-selective, humanized monoclonal antibody in clinical development as a targeted immunotherapy for tumors that overexpress FGFR2b, a splice variant of a receptor for some members of the fibroblast growth factor (FGF) family. Bemarituzumab has been engineered for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) to increase direct tumor cell killing by recruiting natural killer (NK) cells. Clinical results to date suggest that the specificity of bemarituzumab avoids the dose-limiting toxicities that have been seen with less selective pan-FGFR tyrosine kinase inhibitors that act on multiple FGFRs, including FGFR2.

Bemarituzumab is being evaluated in the FGF2b Inhibition in Gastric and Gastroesophageal Junction Cancer Treatment (FIGHT) Phase 1/3 clinical trial, a global registrational study in patients with advanced gastric or gastroesophageal junction cancer whose tumors overexpress FGFR2b or have FGFR2 gene amplification. The Phase 3 portion of the trial is expected to begin in the second half of 2018. In December 2017, Five Prime and Zai Lab announced a collaboration for the development and commercialization of bemarituzumab in Greater China. Zai Lab will manage the Phase 3 portion of the FIGHT trial in China.