In December, when Merck revealed that Lynparza didn’t add benefits to Keytruda in certain non-small cell lung cancer (NSCLC) patients, the trial appeared to be a complete failure. Although the study itself is beyond salvaging, detailed data now raise some hope for the combination in the future.
The trial, coded KEYLYNK-008, tested Lynparza as a maintenance therapy in patients with newly diagnosed squamous NSCLC who had stable disease or better following induction treatment with Keytruda and chemotherapy. Merck in December said it was discontinuing the trial based on the recommendation from an independent data monitoring committee, as the trial was unlikely to succeed.
Neither one of the trial’s dual primary endpoints—progression-free survival or overall survival—were met. The study would have been positive if only one of those goals had been hit.
Turns out, Lynparza reduced the risk of disease progression or death by 23% compared with placebo as a maintenance therapy, although the showing narrowly missed statistical significance. The detailed results were shared Monday at the American Association for Cancer Research annual meeting.
Patients on the Lynparza arm went a median 8.3 months without progression versus 5.4 months for the control group.
When it came to overall survival, Lynparza didn’t show any meaningful improvement. The median overall survival for Lynparza was 19.1 months, versus 18.6 months for placebo. The percentages of living patients were similar between the two arms throughout the trial.
In terms of safety, treatment-related adverse events at grade 3 or above were notably more frequent in the Lynparza arm, at nearly 30%, versus 13% for the control group.
Researchers are now planning to conduct biomarker analyses to see whether any subsets of patients in KEYLYNK-008 may benefit from Lynparza, Ernest Nadal, M.D., Ph.D., from Institut Català d’Oncologia in Spain said in his presentation of the results.
In subgroup analyses not powered for statistical significance, patients with high PD-L1 expressions at a tumor proportion score of at least 50% appeared to have benefited more from the addition of Lynparza, compared with those with lower expressions. Lynparza led to a 31% reduction in the risk of progression or death and a 11% reduction in the risk of death in the PD-L1-high patients.
The original rationale for adding a PARP inhibitor such as Lynparza was that it could increase PD-L1 expression, thereby making the tumor more susceptible to an anti-PD-1 inhibitor like Keytruda, Nadal explained. Besides, in squamous NSCLC, the standard-of-care Keytruda-chemo combo only improved patients' five-year survival rate to 18% in the KEYNOTE-407 study.
In another KEYLYNK-008 subgroup analysis, those who experienced a partial or complete response following the induction Keytruda-chemo regimen appeared to perform better with the addition of Lynparza compared with those who achieved just stable disease. In those who experienced a partial or complete response, Lynparza helped cut the risk of progression or death by 31%.
One obvious consideration for potential future studies, based on biomarker-driven patient selection, is in homologous recombination deficiency (HRD)-positive tumors, Nadal noted. PARP inhibitors are known to work well in HRD-positive ovarian cancer and prostate cancer. But germline HRD alterations in NSCLC are now just being studied, Nadal added.
While the KEYLYNK-008 trial produced a negative result, it still presents an opportunity to learn and to identify whether HRD status played a role in patients’ outcomes, Nadal added.
Besides KEYLYNK-008, Merck recently said that another trial, coded KEYLYNK-006, also failed on both endpoints of progression-free survival or overall survival. That study tested Lynparza alongside Keytruda during the first-line maintenance treatment of metastatic nonsquamous NSCLC.
Despite the two back-to-back blows in the metastatic setting, Merck is still running the phase 3 KEYLYNK-012 study for the Keytruda-Lynparza combo in stage 3 NSCLC. A Merck spokesperson confirmed to Fierce Pharma two weeks ago that the KEYLYNK-012 trial remained ongoing despite the two flops in metastatic disease.