Bristol-Myers Squibb’s (BMS) blockbuster combination of Opdivo (nivolumab) and Yervoy (ipilimumab) has transformed the treatment of metastatic melanoma since 2015 and is constantly expanding in new indications. Many of the FDA labels stipulate Opdivo as monotherapy whereas others are in combination with Yervoy. However, questions about the combination remain. Is the additional toxicity from Yervoy balanced by enough added efficacy? Is the very high cost of the combination justified by the clinical benefit? Are there patient- and indication-specific dynamics that result in a preference for combination over monotherapy?

Opdivo is a PD-1–blocking antibody that so far has gained a label in 11 broad oncology indications in the US. Yervoy is a CTLA-4–blocking antibody indicated for six types of cancer in the US, of which only one is indicated for use as monotherapy. In metastatic melanoma, five-year analysis of the CheckMate 067 study evidenced an overall survival (OS) of 52% for Yervoy and Opdivo versus 44% for Opdivo alone (hazard ratio [HR]: 0.82). In the CheckMate 915 study in the high-risk adjuvant setting, the combination failed to improve recurrence-free survival over Opdivo alone. Analysis of the CheckMate 032 study in small-cell lung cancer shows that while the combination appeared to result in a higher response rate, there was no difference in OS compared to Opdivo monotherapy.

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These results raise further questions about the need for Yervoy as a combination partner. In other tumours, such as non-small cell lung cancer (NSCLC), the combination appears superior, but this is complicated by the fact that in NSCLC there appears to be a correlation between PD-L1 expression levels and the efficacy of immunotherapy. While for cancers of high unmet need, demonstration of superiority for the combination over the standard of care is more likely to suffice, in cancers with several options already available, BMS will have a harder time convincing regulators and payers that the burdensome combination is indeed worth it. Such was the case in mesothelioma, where the combination also received an FDA approval, but with the comparator being chemotherapy rather than Opdivo.

Commercial attributes such as a very high annual cost of therapy (~$120,000–150,000/year as monotherapy and ~$250,000/year as a combination) and a large eligible patient population through multiple label expansions have resulted in noteworthy commercial success for BMS. In 2019, the revenue from Yervoy and Opdivo reached approximately $8B and $1.5B, respectively, worldwide. For all the above reasons, sales of Yervoy have started to plateau and are not forecast to increase at the same pace as Opdivo’s. Yervoy as monotherapy is being used sparingly, resulting in the majority of sales coming from the combination with Opdivo. Other checkpoint inhibitors such as Merck’s Keytruda have shown robust efficacy as monotherapy and threaten the combination’s uptake in several indications. With increasingly more new clinical data questioning the added financial and side-effect burden of Yervoy, its future in the ever-competitive immunotherapy market remains uncertain.