The pivotal Phase 3 KEYNOTE-240 trial evaluating Merck’s (MRK) checkpoint inhibitor anti-PD-1 therapy plus best supportive care, for the treatment of patients with advanced hepatocellular carcinoma (HCC) who were previously treated with systemic therapy, did not meet its co-primary endpoints of overall survival (OS) and progression-free survival (PFS) compared with placebo plus best supportive care.
The improvement of OS results demonstrated in the final analysis did not meet statistical significance and the results of PFS also did not reach statistical significance. The key secondary endpoint of objective response rate (ORR) was not formally tested since superiority was not reached for OS or PFS. The safety profile of KEYTRUDA, in this trial, was consistent with that observed in previously reported studies. Results will be presented at an upcoming medical meeting and have been shared with the U.S. Food and Drug Administration for discussion.
Checkpoint inhibitors such as Merck’s Keytruda and Bristol-Myers Squibb’s (BMY) OPDIVO are breakthroughs being tried for many cancers and succeeded in demonstrating superiority in several of them. However, these results do not mean that these immunotherapy therapies will succeed in all the cases in which clinical trials demonstrated statistical and does not mean that all the patients will be eligible to use them.
Keytruda failed to reach statistical significance in liver cancer, while Exelixis’ (EXEL) targeted drug Cabometyx (cabozantinib) has demonstrated statistically significant results and was approved for liver cancer. The FDA has, indeed, approved cabozantinib (Cabometyx) as a treatment for patients with HCC who previously received sorafenib (Nexavar). The approval was based on positive results from the phase 3 CELESTIAL trial, in which OS was improved by 2.2 months with cabozantinib versus placebo. Median OS with cabozantinib was 10.2 versus 8.0 months for placebo, representing a 24% reduction in the risk of death.
Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center CELESTIAL trial lead investigator, stated, “Patients with this form of advanced liver cancer have few treatment options, particularly once their disease progresses following treatment with sorafenib. Physicians are eager for new options for these patients, and the results of the CELESTIAL trial demonstrate that Cabometyx has the efficacy and safety profile to become an important new therapy in our efforts to slow disease progression and improve treatment outcomes.”
Results from the CELESTIAL trial were first presented at the 2018 Gastrointestinal Cancers Symposium. The study was stopped in October 2017, following a positive interim analysis that showed a significant improvement in OS for cabozantinib. The stoppage was preplanned if the P value for OS reached ≤.021. It did.
The median PFS was 5.2 months compared with 1.9 months for placebo, which was a 56% reduction in the risk of progression or death with the targeted therapy. The ORR was 4% with cabozantinib compared with 0.4% with placebo. When including those with stable disease, the disease control rate with the multikinase inhibitor was 64% compared with 33% for placebo.
In a subgroup analysis of those who received only prior sorafenib for advanced HCC, the median OS was 11.3 months with cabozantinib compared with 7.2 months for placebo. The median PFS in this group was 5.5 months with cabozantinib versus 1.9 months with placebo. (
Discontinued therapy due to treatment-related adverse events (AEs) with cabozantinib was 16% versus placebo 3%. The most common grade 3/4 AEs with cabozantinib versus placebo were palmar-plantar erythrodysesthesia (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase (12% vs 7%), fatigue (10% vs 4%) and diarrhea (10% vs 2%). There was a higher incidence of grade 5 AEs in the cabozantinib arm compared with placebo. Overall, 6 patients had a grade 5 AE in the cabozantinib arm, which included hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism and hepatorenal syndrome. One patient in the placebo group died of hepatic failure.
Cabozantinib was initially approved by the FDA as a treatment for patients with medullary thyroid cancer in 2012. In April 2016 the agent received a new indication as a treatment for patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. This approval was further expanded in December 2017 to include the treatment of patients with advanced RCC in the first-line setting. Numerous other trials exploring the agent remain ongoing.
Keytruda (pembrolizumab) and Opdivo (nivolumab) are being approved for the treatment of many cancers and we expect these checkpoint inhibitors to generate huge sales’ revenues. In the meantime, we also believe that Exelixis’ product cabozantinib has also demonstrated superior effects in the conditions where the product has been approved. We also expect more approvals for cabozantinib alone and in combination with other products, including the checkpoint inhibitors.
As we mentioned above, approved check point protein inhibitors will not succeed in treating all the patients in each condition for which the products have been approved and not all the patients will be eligible to receive them. These immunotherapy products’ adverse effects are different from the targeted drugs such as cabozantinib and the same can be stated vice versa.
Regarding Exelixis, the new approval for cabozantinib for liver cancer is a great deal and the drug will continue to play its role in the treatment of RCC. Needless to say its newly approved antihypertensive product MINNEBRO™ in collaboration with Daiichi Sankyo’s seems badly needed in Japan.