On Saturday night, the controversy around the experimental cancer immunotherapy drug NKTR-214 ratcheted higher following a new data presentation at the American Society of Clinical Oncology annual meeting.
Nektar Therapeutics and Bristol-Myers Squibb, the owners of NKTR-214, are undertaking a hugely expensive program to run nearly two dozen clinical trials spanning 20 indications across nine types of solid tumors. Phase 3 studies in melanoma, kidney cancer, and urothelial cancer are starting soon.
The aggressive drug-development plan is based on a belief that NKTR-214 boosts the efficacy of Bristol’s checkpoint inhibitor Opdivo. Combining the two drugs will benefit more cancer patients, including those with tumors that do not respond to Opdivo on its own, Bristol and Nektar say. If they’re right, it will also make the companies billions of dollars in revenue.
The strategy is controversial, however, because there’s only a small amount of tumor response data from an early-stage, single-arm clinical trial to support the NKTR-214-Opdivo combination approach. An update of this trial on Saturday night at ASCO did little to settle the issue. If anything, the presentation raised more doubts.
In a group of 13 melanoma patients, treatment with NKTR-214 and Opdivo demonstrated a impressive tumor response rate of 85 percent. That means 11 of the 13 patients responded.
But then the companies enrolled another 15 melanoma patients, and the response rate dropped. In the update, 14 of the now 28 treated patients (50 percent) showed significant tumor shrinkage. That means only three of the 15 added patients responded — a concerning drop in the efficacy of the NKTR-214-Opdivo combination.
The study presented at ASCO on Saturday night also included a group of patients with kidney cancer. Here, the initial response rate was 64 percent. Seven of 11 patients responded. But then 15 more kidney cancer patients were enrolled and the response rate dropped to 46 percent. Like with the melanoma group, the falling response rate when kidney cancer patients were added raises questions.
Bristol and Nektar defended the results, saying tumor responses are expected to get better over time. The patients enrolled later in the study have not been followed long enough, but when they are, the companies expect more tumors to shrink, boosting the response rates.
The companies also pointed to data presented Saturday showing NKTR-214 may trigger tumor responses in so-called PD-L1 negative patients who don’t typically respond to Opdivo alone. Five of 12 melanoma patients with PD-L1 negative tumors (42 percent) responded to the combination of NKTR-214 and Opdivo. For the 17 PD-L1 negative kidney cancer patients, the response rate was 53 percent.
But these results are still coming from small numbers of patients, and as more patients are added, the response rates are falling. This makes it hard to determine if NKTR-214 is really improving the response rate that might be seen if Opdivo were used alone.
Running a randomized, controlled study where the combination of NKTR-214 and Opdivo is compared to Opdivo and a placebo is the only way to get definitive results. But Nektar and Bristol chose not to go this route early in the development process.
For Bristol, NKTR-214 is a risky, all-in gamble to save its troubled cancer immunotherapy franchise. Opdivo is Bristol’s crown jewel, with 2017 sales of $5 billion, but the drug has been losing market share to rivals, most notably Merck’s checkpoint inhibitor Keytruda. And Merck is not standing still. The pharma giant is already having great success with combinations of Keytruda and chemotherapy that could make even harder for Bristol and Nektar to win.
So, Bristol and Nektar are taking on a big risk that the response rates seen in the single-arm study of NKTR-214 and Opdivo are real and will improve over time. Meantime, they’ll spend hundreds of millions of dollars to run Phase 3 clinical trials, hoping their gamble — based on scant evidence — pays off when data reads out in several years.
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