Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

Study Cites Opdivo Risk; New Indications OK’d for Tecentriq, Keytruda

As its lead candidate taxis for takeoff, Kite Pharma is expected this coming week to reveal how soon it will reach altitude—as well as more details about another flight plan it is pursuing to fight cancer.

During its third-quarter conference call on Wednesday, Kite should say whether it remains on track to filing a biologics license application for KTE-C19 in non-Hodgkin’s lymphoma by year’s end, as the company committed to in August. Kite has long sought to advance KTE-C19 as the first chimeric antigen receptor (CAR) T-cell therapy to reach the market—a key reason why it is viewed as a leading takeover target—and in recent weeks, has discussed manufacturing and commercial preparations for the therapy.

At an investor conference a few weeks back, Kite also offered details on its pipeline of allogeneic T cell receptor (TCR) therapies. Furthest along is KITE-718, for which the company said last month it expects to file an IND this year. KITE-718 targets next generation MAGE A3/A6 for non-small cell lung cancer (NSCLC) and bladder cancer. Another Kite TCR candidate, KITE-439, is designed to fight cervical cancer and head and neck cancer by targeting HPV-16 E7; an IND is expected in 2018.

Unlike CAR T-cell therapies, which are autologous, the TCR treatments would be allogeneic, capable of being manufactured and stored without sampling individual patients.

TCR would also be cheaper to produce. Cellectis CEO Andre Choulika last year told Bloomberg News his company could make an allogeneic CAR T therapy at a per-patient cost of $15,000, with plans to shrink that to $5,000 as the process is standardized.

“When you consider that the autologous products will likely be priced for multiple hundreds of thousands per patient, that would be a meaningful thing,” Brad Loncar, CEO of Loncar Investments, told GEN.

But only, he added, if allogeneic CAR T therapies can be shown to be effective.

“It is possible the allogeneic approach might have some success in leukemias like ALL, they will have a more difficult time in lymphomas and other cancers because the cells need to show durable persistence and that will be allogeneic’s weak point,” Loncar added.

Yet companies that can show effectiveness can potentially catapult to immuno-ocology leadership: “We believe that companies with T-cell therapies that are applicable to a broad patient population and can be easily manufactured could be a major disruptor in oncology and other disease areas,” John Newman, Ph.D., of Canaccord Genuity said in a report.

As for KTE-C19, Kite plans to present additional clinical data on the CAR T therapy at next month’s American Society of Hematology (ASH) Annual Meeting—namely, interim results from the pivotal Phase II ZUMA-1 in chemorefractory primary mediastinal B-cell lymphoma and transformed follicular lymphoma, both forms of aggressive NHL.

Kite also said it will share additional information on the novel T-cell manufacturing process for KTE-C19 it is using in the ZUMA-3 and ZUMA-4 clinical trials assessing the candidate in relapsed or refractory ALL. At its October 18 investor conference, Kite declared its ability to produce KTE-C19 at commercial scale, estimating it could supply more than 4,000 treatments per year, and expand on that capacity quickly if needed.

“Although much work remains, it is clear that institutions, industry, FDA, and payors are preparing for CAR Ts to come to market, which could be as soon as 2017,” Jefferies said October 19 in a report on Kite.

Among developers of already-marketed immuno-oncology drugs, Bristol-Myers Squibb (BMS) received more unwelcome news for its Opdivo® (nivolumab). A study published Thursday in The New England Journal of Medicine reported the deaths of two melanoma patients from fatal myocarditis through a combination of Opdivo and Yervoy (ipilimumab). The study added that myocarditis occurred in 0.27% of patients treated with the combination, “which suggests that our patients were having a rare, potentially fatal, T-cell–driven drug reaction.”

“Although immune checkpoint inhibitors improve outcomes for patients with metastatic melanoma, clinicians need to be vigilant about recognizing nonspecific symptoms in patients treated with combination immunotherapy,” Ramya Ramaswami, M.B.B.S., M.R.C.P., M.P.H., advised on NEJM’s physician blog.

BMS plans to release additional data on the Opdivo-Yervoy combo this coming week, at the 2016 Society for Immunotherapy of Cancer 31st Annual Meeting, and next month at ASH.

Two other pharmas with already-marketed cancer immunotherapies won FDA approvals for new indications.

Merck’s Keytruda® (pembrolizumab) on October 24 was approved for first-line treatment of patients with metastatic NSCLC, whose tumors have high PD-L1 expression—a tumor proportion score of 50% or more, based on an FDA-approved test—with no EGFR or ALK genomic tumor aberrations.

Six days earlier, Genentech, a member of the Roche Group, was told its Tecentriq® (atezolizumab) was approved for metastatic NSCLC with disease progression during or following platinum-containing chemotherapy, and have progressed on an FDA-approved targeted therapy if their tumor has EGFR or ALK gene abnormalities. Approval was based in part on the Phase III OAK trial, which showed that people taking Tecentriq lived a median of 13.8 months, 4.2 months longer than those receiving docetaxel chemotherapy.

“The observed survival for Tecentriq for a Phase III study in this lung cancer population is unprecedented,” Dan Chen, M.D., Ph.D., global head of cancer immunotherapy development at Genentech, told GEN. “Tecentriq forms the foundation of our cancer immunotherapy program. With these results, I’m even more excited about the future of cancer immunotherapy.”

By inhibiting PD-L1, Tecentriq blocks its interaction with PD-1, as well as with B7.1—but not with PD-L2, as inhibition of PD-1 would do. “Our hypothesis is that blocking the interaction with PD-1 and B7.1 but not interfering with the PD-L2 interaction may help to elicit durable responses while minimizing treatment-related safety issues,” Dr. Chen said.

In recent weeks, several companies have signaled growing interest in cancer immunotherapies, the largest being Johnson & Johnson: “We currently have 15 immuno-oncology assets in development, including eight that are in the clinic,” William N. Hait, M.D., Ph.D., global head, Janssen R&D, disclosed October 18 during J&J’s quarterly conference call. He said the company was focused on four “critical” areas—vaccines, T-cell checkpoint inhibitors, T-cell redirection and myeloid mechanisms of action.

Ten days later, Astellas Pharma revealed it plans to acquire Ganymed Pharmaceuticals, the developer of a new class of immunotherapeutic cancer drugs called Ideal Monoclonal Antibodies (IMABs) for solid tumors. Astellas will pay up to €1.282 billion ($1.4 billion) for Ganymed.

Most recently on Wednesday, Celldex Pharmaceuticals agreed to acquire Kolltan Pharmaceuticals for up to $235 million, which would expand the buyer’s immuno-oncology and antibody portfolio.

Earlier, RXi Pharmaceuticals positioned itself for a possible immuno-oncology expansion by signing an exclusive option agreement giving it until April 5, 2017, to acquire MirImmune. Last year, MirImmune signed an exclusive license agreement for RXi's novel and proprietary sd-rxRNA technology for developing cell-based cancer immunotherapies.

Among recent collaborations, the Merck KGaA/Pfizer co-developed immune checkpoint inhibitor Avelumab will be assessed in combination with Vaccinex’s VX15/2503 through a clinical collaboration whose value was not disclosed. Also of undisclosed value is the partnership by Daiichi Sankyo and AgonOx to develop an undisclosed immuno-oncology target. And NeoTX will develop Active Biotech’s cancer immunotherapy candidate Anyara (naptumomab estafenatox) for up to $71 million.

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