Game over: Bristol Myers, Nektar end $3.6B immuno-oncology program after 2 more late-stage flops

Bristol Myers Squibb and Nektar have read the last rites to their huge, failed cancer collaboration. With two more late-stage trials failing, the partners have ended clinical development of a combination they once saw as the future of immuno-oncology.

The chances of Bristol Myers’ $1 billion upfront bet on bempegaldesleukin, a prodrug of PEGylated IL-2, paying off shrank last month. One month ago, Bristol Myers revealed a combination of Nektar’s bempeg and its Opdivo failed to improve on the progression-free survival and objective response rate achieved by the PD-1 checkpoint inhibitor as a single agent in previously untreated melanoma patients. The failure triggered the end of another study and raised serious doubts about the future of the combination.

Bristol Myers and Nektar confirmed those doubts late Thursday, revealing the combination has failed in two other clinical trials. In one study, the partners compared their drug cocktail to the investigator’s choice of two tyrosine kinase inhibitors (TKIs), namely Exelixis’ Cabometyx and Pfizer’s Sutent, in metastatic renal cell carcinoma (RCC) patients. The trial looked at intermediate/poor risk and all-risk populations. 

A preplanned interim analysis found the investigational combination failed to improve on the overall survival achieved by the TKIs in either population. Faced with the failure, Bristol Myers and Nektar have decided to unblind the trial and perform no more overall survival analyses.

Bristol Myers and Nektar also reported the failure of the combination in patients with cisplatin-ineligible, locally advanced or metastatic urothelial cancer. The single-arm phase 2 clinical trial failed to achieve the objective response rate needed to support the continuation of the program.

After going 0 for 3, Bristol Myers and Nektar have decided to discontinue all other studies of the drug combination. The list of studies now winding down include a pivotal program in muscle-invasive bladder cancer and a pair of phase 1/2 trials in RCC and pediatric tumors. Shares in Nektar fell 17% to around $5 after hours, wiping out the small gains they made after news of the melanoma failure dropped.  

The discontinuation of the clinical development program confirms the failure of one of the big bets of Thomas Lynch's time as Bristol Myers’ chief scientific officer. Bristol Myers paid $1 billion upfront, made a $850 million stock purchase at $102.60 a share—a price it only briefly hit in the immediate afterglow of the deal—and committed up to $1.8 billion in milestones, all for a 35% split of global profits. 

Bristol Myers put together the mammoth financial package in the belief IL-2 was one of three validated mechanisms in immuno-oncology, the others being PD-1 and CTLA-4. The IL-2 cytokine is the first cancer immunotherapy, with the FDA approving a recombinant form in the early 1990s, but problems such as its poor drug-like properties and toxicity limited uptake. Bempeg was designed to eliminate those problems. 

One question now is whether the failure of bempeg to live up to that promise wipes out the IL-2 field, as mostly happened to one-time immuno-oncology start target IDO after the failure of Incyte’s epacadostat, or if other programs push on and deliver better results. 

Sanofi made a big bet on the IL-2 space early in 2020 when it closed its $2.5 billion takeover of Synthorx. The deal gave Sanofi control of THOR-707, a recombinant IL-2 molecule that last year delivered phase 1/2 data in solid tumors that analysts at Jefferies called “intriguing.”