Weighing Efficacy vs. Tolerability: Lenvima + Keytruda in Advanced ccRCC

Conclusion: Despite its toxicity, the overwhelming efficacy advantage of the Keytruda + Lenvima regimen in first-line (1L) treatment of advanced clear cell renal cell carcinoma (ccRCC) puts it in a position to lead the market in this indication. Tolerability concerns will limit its share.

Winning an FDA approval in August 2021, the combination of Lenvima (lenvatinib, Merck + Eisai) and Keytruda (pembrolizumab, Merck) is the most recently approved TKI/IO therapy with an NCCN category 1 recommendation for 1L treatment of advanced ccRCC. This is the third TKI/IO combination to secure an FDA approval and category 1 recommendation, with Inlyta (axitinib, Pfizer) + Keytruda being approved in April 2019, and Cabometyx (cabozantinib, Exelixis) + Opdivo (nivolumab, BMS) approved in January 2021. The approvals and category 1 recommendations of these regimens span all risk groups. These regimens have since bumped sunitinib (Sutent by Pfizer, which went generic in August 2021) from a category 1 recommendation to a category 2A recommendation. Our comparison of the category 1 TKI/IO regimens in this indication shows that although the Lenvima + Keytruda regimen may be more toxic than the others, this disadvantage is modest relative to its major improvement in efficacy. Our analysis is based on phase 3 clinical trial data (CLEAR, CheckMate 9ER, and KEYNOTE-426).

Historically, new regimens with clinical innovation over 10% achieve strong patient share. Lenvima + Keytruda shows 13.4% clinical innovation over Inlyta + Keytruda, driven by improved efficacy.

Lenvima + Keytruda should excel commercially in patients who are able to tolerate it. Dose reductions and interruptions will help manage the toxicity of this regimen and expand its usage to patients who may not able to tolerate it otherwise.

For the clinical benefit that Lenvima + Keytruda provides relative to Inlyta + Keytruda, its higher price is reasonable. Because of this, it falls within the “cloud” of drugs that have historically achieved good market access, and we predict that Lenvima + Keytruda will perform well commercially.

As a side note, Cabometyx + Opdivo is likely to capture share in this indication as a more tolerable alternative to Lenvima + Keytruda, with its efficacy improvement driving its 7.1% clinical innovation over Inlyta + Keytruda.

Finding the Right Price for a Drug across Multiple Indications; Learnings from Keytruda

Previously, Equinox has described a hypothetical exercise in which a development team attempts to find an optimal price for an agent that is in development in multiple indications.

Here we repeat this exercise with a real-world example, Keytruda.

Keytruda has been approved for a variety of indications.

These indications differ in the size of the addressable patient population (bubble size), the level of unmet need (y axis) and, most importantly, the degree to which Keytruda delivers benefit to patients (x axis).

Finding the right price-per-vial across diverse indications is challenging. Equinox’s analytical tools allow product teams to quantify the value delivered in each population. When we plot the incremental clinical benefit delivered against incremental cost for successful agents, we see the following “cloud” relationship:

Each point represents a new agent in a specific patient population.

Equinox predicts that emerging agents that map within this cloud will receive favorable reimbursement, but agents that land below the cloud risk significant push-back from payers in those indications. Points above the cloud represent indications where the agent is under-priced.

Compared to these exemplars, Keytruda’s various indications map as follows:

Keytruda’s price appears appropriate for Gastric, Head and Neck, and Lung Cancer. As a consequence, it offers poor value for money in RCC and Endometrial, and leaves money on the table in HCC and Melanoma. Overall, the price point appears optimized.

Equinox’s analytical tools allow product teams to assess the trade-offs inherent in arriving at a price for any agent in development for multiple indications.