The PD-1/L1 inhibitor class of drugs has vastly improved care for many patients with cancer, but some meds in the class have posted trial failures lately. At the American Society of Clinical Oncology's recent annual meeting, two trial failures for class leaders were on display.
For Merck's Keytruda, the drug couldn't add enough benefits on top of chemotherapy when tested in patients with nonsquamous non-small cell lung cancer (NSCLC) who had developed resistance to EGFR inhibitors such as AstraZeneca’s Tagrisso
In the KEYNOTE-789 trial, a combination of Keytruda and chemotherapy only reduced the risk of death by 16% over chemo alone in patients with tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC. Patients who took Keytruda lived a median 15.9 months, versus 14.7 months for control. The advantage wasn’t statistically significant.
The Keytruda-chemo combo reduced the risk of progression or death by 20%, which again didn’t meet statistical significance. The median progression-free survival length between the two arms was similar.
About half of patients enrolled in the study had failed on Tagrisso, the most potent EGFR inhibitor today, a Merck spokesperson noted in a statement to Fierce Pharma. This suggests that poor prognosis factors may have contributed to the unfavorable result.
Also in immunotherapy-pretreated NSCLC, Merck and partner Eisai are combining Keytruda with Lenvima in the phase 3 LEAP-008 trial. The study bears a primary completion date this August, according to ClinicalTrials.gov.
Separately, the use of Roche’s PD-L1 inhibitor Tecentriq on top of Exelixis’ TKI Cabometyx not only failed to offer any extra benefit in previously treated kidney cancer, but it instead added toxicity.
In the CONTACT-03 trial, patients with previously treated kidney cancer who got the Tecentriq-Cabometyx combo and those who received Cabometyx monotherapy had almost the same life expectancy. By the time of data cutoff, both arms had a 34% death rate.
On top of the lack of additional efficacy, side effects led 16% of patients to discontinue treatment in the combo arm, versus 4% for the Cabometyx group. The rate of serious adverse events was also higher for the Tecentriq pairing.
Combinations with PD-1 agents have become the standard of care in newly diagnosed kidney cancer. These include Bristol Myers Squibb and Exelixis’ Opdivo-Cabometyx combo. All CONTACT-03 participants had progressed during or after prior PD-1 treatment.
The CONTACT-03 results “prompt caution” for the approach of continuing PD-1/L1 treatment after prior failure by adding directly on a standard control arm, the CONTACT-03 researchers wrote in an abstract.
But William Blair analyst Andy Hsieh, Ph.D., found a silver lining—though not for Tecentriq—from the failed CONTACT-03 trial.
Cabometyx alone showed a median progression-free survival of 10.8 months and an overall response rate of 41%, which were better than data from previous trials.
“Given the Contact-03 study represents the first [phase 3] study that investigates Cabometyx’s clinical profile in an entirely [immune checkpoint inhibitor]-treated population, which in our view faithfully captures the real-world prescribing pattern, we believe the study will likely establish Cabometyx as the most reasonable choice for patients, following relapse on [immune checkpoint inhibitor] treatment,” Hsieh wrote in a Monday note.
Meanwhile, kidney cancer doesn’t look like Tecentriq’s area of specialty. The drug recently also failed in the IMmotion010 trial when used as an adjuvant therapy in patients with kidney cancer at high risk of developing metastasis after surgery.
In a statement to Fierce Pharma, a spokesperson at Roche’s Genentech said the company looks forward to the next phase 3 readout from the Exelixis-partnered CONTACT trial program. That will be CONTACT-02 in metastatic castration-resistant prostate cancer. Keytruda recently suffered a series of setbacks in prostate cancer.