Regulatory, Setbacks

After kickback from the FDA, Bristol-Myers yanks its Opdivo/Yervoy BLA for high TMB approach to lung cancer

Bristol-Myers Squibb has had a hard time winning analysts over to its strategy for carving out a higher market share for its checkpoint combo in non-small cell lung cancer. And now you can add the FDA to the list of skeptics requiring more data to convince them.

In their Q4 release Thursday morning Bristol-Myers Squibb says it is yanking its BLA for Opdivo combined with Yervoy for frontline NSCLC cases with high tumor mutational burden — or TMB — after talks with the agency convinced them they needed more data to highlight the connection between TMB and PD-L1.

Their statement:

This analysis will require availability of the final data from Checkmate -227, Part 1a (Opdivo plus low-dose Yervoy or Opdivo monotherapy versus chemotherapy in patients whose tumors express PD-L1), which the company anticipates will be available in the first-half of 2019. Since these data from Checkmate -227, Part 1a, will not be available within the review cycle of the current application the company decided to withdraw.

Bristol-Myers’ stock took a 2.4% hit in trading ahead of the opening bell.

Longtime observers have been puzzling out the whole TMB approach, which AstraZeneca has also been turning to in the wake of its own PD-L1/CTLA-4 setbacks with Imfinzi and tremelimumab. Bristol-Myers redesigned its critical late-stage trial to shift to TMB, and it has not played out in their favor — so far.

After Merck seized the lead in lung cancer with its superior Keytruda/chemo combo, Bristol-Myers’ team led by R&D chief Tom Lynch has been struggling to make a comeback. Typically, the FDA has been wide open — at least in recent years — to accelerated approvals for cancer drugs. In this case, Bristol-Myers found that the bar has been raised as physicians employ a growing number of PD-1/L1s in their practice.

Credit Suisse’s biopharma team took at look at the news and concluded that, on balance, Bristol-Myers’ move raises fresh concerns.

We did not think an approval for that filing would have made much of a near-term commercial impact anyway, but it does raise new questions on the company’s overall strategy and approach in 1L NSCLC.

In an update last October, researchers for Bristol-Myers noted that the hazard ratio for their combo was roughy identical for high and low TMB groups getting the combo, but the overall survival rate was 23 months for high TMB patients at 16.7 months in a chemo arm with high TMB. There was also a difference of a few months for the low TMB group.

The setback comes just weeks after Bristol-Myers announced its plan to acquire Celgene for $74 billion. And today there was a big focus on the top late-stage drugs they will gain from Celgene: Ozanimod, with a Q1 refiling plan; the CAR-T Liso-cel (JCAR017 from the Juno buyout), with an H2 2019 filing plan; and the anti-BCMA CAR-T bb2121 partnered with bluebird, filing in H1 2020. All that has to counter questions revolving around the IP for Revlimid.

The latest problem with the Opdivo franchise overshadowed the company’s Q4 and 2018 financial report, which highlighted a 10% hike in sales. Opdivo itself earned $6.7 billion last year, up from just under $5 billion in 2017. The rest of the approved slate pf PD-1/L1s has been struggling to get into the same league with Merck and Bristol-Myers Squibb.


Image: Thomas Lynch at BIO 2018. ROB TANNENBAUM for ENDPOINTS NEWS


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Sr. Manager, Regulatory Affairs, CMC
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