- Bristol-Myers Squibb and Nektar Therapeutics plan to advance a combination of Opdivo and the biotech's experimental immunotherapy NKTR-214 into Phase 3 testing in first-line melanoma, kidney and bladder cancers, forging quickly ahead after announcing updated results Saturday from an early-stage study.
- The decision to move forward with late-stage testing was triggered by response rates across the three cancer types hitting pre-specified levels in a dose-expansion phase of the Phase 1/2 trial. Yet the small number of patients and complex data set raise questions about how that signal will hold up over time.
- In melanoma, the companies aim to start later this year a large pivotal study comparing the combination versus Opdivo alone in over 700 patients. Trials in kidney and bladder cancers are in the works, but have yet to be finalized.
Bristol-Myers bet big on Nektar's drug back in February, paying $1.85 billion upfront for partial rights to the immunotherapy. That investment greatly raised expectations heading into Saturday's update from the companies' Phase 1/2 study of the combination with Opdivo (nivoluamb).
The data presented shows the two drugs together elicited response rates in the 46% to 60% range across all efficacy evaluated patients with the three cancer types. Despite those early positive signs, however, Bristol-Myers and Nektar could be advancing on shaky ground.
Investors certainly seemed to think so, pushing shares in Nektar down by more than 40% Monday morning.
Data showed half of the 28 immunotherapy-naive melanoma patients treated with Opdivo and the selected dose of NKTR-214 responded as of data cut-off. While that 50% response rate is higher than what has been observed previously with Opdivo monotherapy in melanoma, it is lower than previous results from fewer patients and may disappoint some investors.
Per the study design, Bristol-Myers and Nektar needed to see 10 out of 13 patients in the first stage of the dose-escalation phase respond. Eleven did, opening up further enrollment into the second stage. Only three of the subsequent 15 patients treated saw a response by time of analysis, yielding the 50% rate.
The story was similar in renal cell carcinoma, where the initial bar for efficacy was cleared but overall response rates for both stages combined checked in lower.
Clinical efficacy of Opdivo plus NKTR-214, as of May 29
|Overall response rate (ORR) in stage 1 (#)||ORR in all efficacy evaluable pts. (#)||ORR in PD-L1+ pts. (#)||ORR in PD-L1 neg. pts. (#)|
|Melanoma||85% (11/13)||50% (14/28)||62% (8/13)||42% (5/12)|
|Renal cell carcinoma||64% (7/11)||46% (12/26)||29% (2/7)||53% (9/17)|
|Bladder cancer||60% (6/10)||60% (6/10)||60% (3/5)||60% (3/5)|
SOURCE: Nektar Therapeutics
Nektar emphasized, however, that median time on study for those additional patients was short, meaning further responses could occur as those patients spend more time on treatment. As it stands now, however, Bristol-Myers and Nektar are committing to a large Phase 3 program on a signal generated by several dozen patient responses.
Importantly, though, both PD-L1 negative and PD-L1 positive patients responded to treatment — an encouraging sign for a combination designed to broaden Opdivo's efficacy.
A handful of patients who tested PD-L1 negative at baseline converted to PD-L1 positive status at week 3. Since NKTR-214 is designed to increase expression of the PD-1 protein, this offers some sign that the experimental drug could successfully alter the tumor microenviornment in a way that complements the action of Opdivo.
Overall, 275 patients have been treated at the selected Phase 2 dosing of NKTR-214 and Opdivo, many of whom were in cohorts too early to evaluate for efficacy. The companies are also testing the combination in non-small cell lung cancer and triple-negative breast cancer, as well as later lines of immunotherapy-refractory patients.
Bristol-Myers and Nektar are progressing their combination quickly, not entirely surprising given the fast-moving nature of the immunotherapy field. Yet a recent Phase 3 failure from Merck & Co and Incyte's pairing of Keytruda and epacadostat highlight the pitfalls that can result from relying on signs of efficacy in single-arm studies.
Editor's note: This article has been updated to include mention of the initial stock market reaction Monday to Nektar and Bristol-Myers Squibb's results.