Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

NSCLC is “Major Battlefield” as Merck, AstraZeneca, and Pfizer Hunt for Advantage

As Mark Twain might say if he were running Bristol-Myers Squibb (BMS), the reports of Opdivo’s death are greatly exaggerated.

During a presentation Thursday at the Leerink Partners Immuno-Oncology Roundtable Conference, Fouad Namouni, M.D., BMS svp and head of oncology, said Opdivo’s failed Phase III trial in non-small-cell lung cancer (NSCLC) has not made BMS rethink its approach to developing the blockbuster drug.

“I would say our overall strategy has not changed,” Dr. Namouni told analysts.

That approach, he said, has advanced from second-line treatment into combination therapies, and first-line approaches like the one that missed its primary endpoint in the pivotal Checkmate-026 trial assessing Optivo as a first-line treatment for non-small-cell lung cancer (NSCLC).

“Moving forward to first line, we knew the bar was high. Chemotherapy in first line is more active than in second line. The patient population is slightly different than second line and we wanted to add some monotherapy questions and combination questions,” Dr. Namouni added.

He also noted that several additional trials involving Opdivo are in progress, including Checkmate-227, assessing an Opdivo-Yervoy (ipililumab) combination as a first-line treatment for NSCLC. On Tuesday, BMS joined Nektar Therapeutics to announce new Phase I/II studies that will assess the combination of Opdivo plus NKTR-214 in five tumor types.

The fallout from Checkmate-026 goes beyond the 28% stock slide since the outcome was reported August 5—BMS shares closed Thursday at $53.87—to expected weakness against rivals.

“The negative results from Bristol’s CheckMate-026 study will give competing immuno-oncology drugs time to catch up to Opdivo,” Morningstar analyst Damien Conover, CFA, told GEN.

Especially Keytruda® (pembrolizumab). At the European Society for Medical Oncology (ESMO) 2016 Congress in Copenhagen, to be held October 7–11, Merck & Co. will present details of the Phase III data it trumpeted in June—superior progression-free survival vs. chemotherapy in NSCLC.

As Conover notes, Merck targeted patients with PD-L1 expression greater than or equal to 50%, vs. the more challenging 5% cut-off point used by BMS. In October, BMS is expected to reveal whether Opdivo worked at 5% when it releases a complete dataset from CheckMate-026.

“We believe Merck will have a longer first-mover advantage in the first-line lung cancer market as Bristol may need to wait for data from the Checkmate-227 (data likely in mid-2017) to file Opdivo in first-line lung cancer,” Conover added. “As a result, we are increasing Merck’s market share in lung cancer and reducing Bristol’s share.”

On Wednesday, Merck presented updated positive data from the Phase I portion of the ECHO-202 trial, assessing a one-two punch of Keytruda and epacadostat, Incyte’s selective IDO1 enzyme inhibitor. The combo showed an overall response rate of 58% in 19 patients with treatment-naïve advanced melanoma.

“Merck is already making progress in positioning Keytruda as the one to beat here,” Louis Perdios, associate consultant with Blue Latitude Health, told GEN. “Although Keytruda is not going to supersede Opdivo in future sales according to current projections, it is certainly going to gain substantial ground.”

Merck aims to do just that when it announces data in December from its KEYNOTE-024 trial of Keytruda in advanced NSCLC. In addition to those results, Perdios said, Opdivo’s fate will hinge on developments from other competing drugs, including:

  • The Pfizer/Merck KGaA co-developed Avelumab, which has launched Phase III first-line trials in recurrent/stage IV NSCLC (JAVELIN LUNG 100) and ovarian cancer (JAVELIN OVARIAN 100). Avelumab has achieved FDA Breakthrough Therapy status for Merkel cell carcinoma. 
  • AstraZeneca’s Durvalumab, whose late entry to market and delays in some trials may hurt the candidate despite an extensive clinical program beyond NSCLC, on head and neck, bladder, gastric, pancreatic, HCC and blood cancers.
  • Roche’s Tecentriq (atezolizumab), an anti-programmed death-1 ligand-1 (PD-L1) monoclonal antibody. “PD-L1 as a biomarker in personalized cancer immunotherapy carries a lot of weight and will help a lung cancer approval for Roche,” Perdios said.

“The major battlefield is NSCLC,” Perdios said. “It represents a large proportion of the market and a lot of patients. Biomarkers will also be crucial in securing approvals.”

Trial results from those and other drugs should surface on the new “Cancer Immunotherapy Clinical Trials Network” registry, recommended among 10 research goals for Vice President Joe Biden’s “Cancer Moonshot” by a 28-member Blue Ribbon Panel formed by NCI’s National Cancer Advisory Board. The NCI accepted the panel’s recommendations on September 7.

This past week, three efforts to develop T-cell treatments made news. bluebird bio and Medigene launched a $1 billion-plus collaboration to develop cancer immunotherapy candidates against four undisclosed targets, with bluebird using Medigene’s T-cell receptor platform.

Kite Pharma on Tuesday trumpeted positive topline data for its lead product candidate KTE-C19 in the Phase II portion of a Phase I/II trial in patients with non-Hodgkin's lymphoma (NHL). KTE-C19 achieved a combined objective response rate of 79%, including 52% complete remission, in patients with chemorefractory aggressive NHL.

Also, Adaptimmune Therapeutics signaled plans to expand its T-cell pipeline by partnering with The University of Texas MD Anderson Cancer Center to develop therapies based on the company’s Specific Peptide Enhanced Affinity Receptor (SPEAR®) platform. Therapies will include MAGE-A10, which is in Phase I/II study for advanced stage NSCLC; and future clinical stage first- and second-generation SPEAR T-cell therapies such as MAGE-A4 across bladder, lung, ovarian, head and neck, melanoma, esophageal, and gastric cancers.

Betting on an alternative immuno-oncology approach, Boehringer Ingelheim on Wednesday agreed to co-develop ViraTherapeutics’ oncolytic virus therapy platform and lead candidate. The up-to-€210 million ($225 million) collaboration gives Boehringer Ingelheim rights to acquire the privately held Austrian biotech upon conclusion of Phase I development of VSV-GP.

Boehringer also doubled down on checkpoint inhibitors, saying Thursday it will join the Sarah Cannon Research Institute to study two checkpoint inhibitors—the monoclonal antibodies BI 754091 (anti- PD-1) and BI 754111 (anti-LAG 3)—in NSCLC and other cancers.

The checkpoint approach has paid off for one German startup, as iOmx Therapeutics said September 22 it raised €40 milion ($45 million) in series A financing. Investors include Merck Ventures, the venture arm of Merck KGaA, Wellington Partners, and co-leaders MPM Capital and Sofinnova Partners. iOmx says it’s developing cancer drugs through its own platform, which uses using clinical tumor samples and tumor-infiltrating lymphocytes to identify new targets: “Many of them exhibit stronger inhibition of T cell killing than PD-L1 in classical assays.”

Another alternative I/O approach, inhibition of the E2 receptor 4 (EP4), will get further study by Eisai at its recently launched Eisai Andover innovative Medicines (AiM) Institute. The discovery innovation unit will focus on discovering and developing precision medicines for cancer, as well as dementia and autoimmune diseases.


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