BMS shifts towards precision medicine

On 1 August, Bristol-Myer Squibb (BMS) announced that the US Food and Drug Administration (FDA) had approved the use of its programmed cell death 1 (PD-1) inhibitor Opdivo (nivolumab) in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Opdivo’s main rival immunotherapy Merck & Co.’s Keytruda (pembrolizumab) obtained a similar nod for CRC in May 2017. However, in that instance, the FDA granted Keytruda a broader label as it was cleared in all microsatellite instability-high (MSI-H) solid tumours, regardless of tumour location. In clinical trials, responses to Keytruda were registered in endometrial, biliary, gastric, and pancreatic MSI-H cancers.

This represents the last chapter in a long head-to-head battle between the two PD-1 inhibitors that has been continuing since the drugs were approved for their original indication, melanoma. In addition to its label for all MSI-H tumours, Keytruda is approved for six different tumour types, all overlapping with Opdivo. BMS’s immunotherapy is also approved for renal cell carcinoma, representing a total of seven distinct tumour types.

Although faster approvals and strong clinical results have given BMS’s Opdivo a lead, its future dominance in the PD-1 space is now uncertain. The figure below depicts company reported sales, with H1 2017 sales and projections for H2 2017 showing a faster growth trajectory for Keytruda over Opdivo. Although Opdivo was still the top-selling PD-1 inhibitor in the first six months of 2017, Keytruda closed the gap, with sales growing by 160% compared with the previous year. In contrast, despite its new approvals, Opdivo experienced only 42% growth.

Until 2016, Opdivo had a huge lead over Keytruda, mainly due to the different strategies adopted by BMS and Merck & Co in non-small cell lung cancer (NSCLC), one of the most common forms. Merck & Co. took a personalised approach and designed Keytruda’s trials by selecting patients based on biomarker expression (programmed death-ligand 1 [PD-L1] expression) to define those more likely to benefit from the treatment.

On the other hand, BMS adopted a more generalised approach for Opdivo, investigating the drug in all newcomers. As a consequence, the Keytruda label for second-line use in NSCLC was initially restricted to patients with up ≥50% PD-L1 expression, while Opdivo was available to all NSCLC patients. Merck & Co decided to adopt a long-term, more sustainable strategy for Keytruda, whereas BMS’s strategy led to a better performance for Opdivo in the short-term, resulting in higher sales in 2015 and 2016.

BMS’ approach took a hit when Opdivo failed to obtain a label extension as a first-line treatment in newly diagnosed NSCLC patients, following the failure of the Checkmate-026 trial. In this study, BMS again tried to target a larger patient pool, using a PD-L1 threshold inclusion of 5%. Keytruda was able to obtain a first-line nod in NSCLC by using a higher threshold and pursuing a smaller population (patients with PD-L1 expression ≥50%, still accounting for approximately 30% of NSCLC patients) in October 2016.

This approval has pushed the sales of Keytruda in the first half of 2017 and limited further growth of Opdivo. Recently, in May 2017, Keytruda gained an additional approval as a first-line combination therapy with pemetrexed and carboplatin in NSCLC, irrespective of PD-L1 expression. The larger pool of patients is expected to further boost the sales of the agent, allowing Keytruda to surpass Opdivo, possibly as early as next year.

The 2017 half year and projected sales support the precision-medicine approach used by Merck & Co. over BMS’ mass-marketing approach. However, the recent biomarker-driven approval of Opdivo in MSI-H CRC, representing approximately 5% of CRC patients, suggests that BMS has learned from its own mistakes and is now changing the drug development strategy for its PD-1 inhibitor. GlobalData finds that BMS is now using biomarker stratification in the majority of its pivotal trials for Opdivo, including head and neck, hepatic, and gastric cancer. This strategy shift keeps the PD-1 race open to further developments.