Rybrevant and Exkivity: two highly innovative new therapies to treat EGFR Exon 20 Insertion positive mNSCLC

Conclusion: Two highly innovative new therapies, Rybrevant and Exkivity, were approved by the FDA within four months of each other. We think that Janssen’s Rybrevant is likely to come out on top in this competition.

EGFR- positive NSCLC has several targeted options for treatment such as Tagrisso (osimertinib) and Tarceva (erlotinib). However, EGFR exon 20 insertion positive mNSCLC, for which existing EGFR TKIs are ineffective, is still treated with chemotherapy.  These patients have a poor prognosis and this mutation affects approximately 2% of those diagnosed with NSCLC.

Janssen’s bispecific antibody therapy, Rybrevant (amivantamab- vmjw), was launched May 2021 and Takeda’s oral tyrosine-kinase inhibitor, Exkivity (mobocertinib), was launched September 2021. Both agents are approved for EGFR Exon 20 insertion patients who have progressed on or after platinum-based chemotherapy. We reviewed data from the phase I/II approval trials for these two agents, CHRYSALIS (Rybrevant) and EXCLAIM (Exkivity). These drugs were granted accelerated approval by the FDA based on ORR and response duration.

Both Rybrevant and Exkivity show significant Clinical Innovation over the previous standard of care, docetaxel, with 19.0% and 17.4% improvement respectively. New agents with Clinical Innovation over 10% historically achieve strong patient shares. These drugs have similar efficacy (mOS, mPFS and response rates) and WAC prices. However, they differ notably in safety/tolerability, with Rybrevant having a significant advantage over Exkivity.   Rates of serious diarrhea are high in patients who took Exkivity, and it has two black box warnings for cardiovascular safety - QTc prolongation and torsades de pointes (an abnormal heart rhythm that can lead to sudden cardiac death). Rybrevant is administered as an IV infusion every two weeks, while Exkivity is taken orally once a day.

Rybrevant was approved four months ahead of Exkivity, and is vying for more approvals in all-comers (i.e., beyond the Exon 20 mutation) in 1L EGFR+ mNSCLC vs. Tagrisso with a phase III trial in progress, in addition to phase III trials in 2L EGFR+ mNSCLC. It also has phase II trials in other cancers, including esophageal and gastric.

Exkivity appears to be further behind in earlier phase trials, including a phase I/II trial in solid tumors harboring EGFR or HER2 mutations and phase I studies in renal and hepatic impairment. The Janssen strategy is to compete in the broader EGFR+ NSCLC population, whereas Takeda pursues opportunities in other malignancies and therapeutic areas. 

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.