Merck & Co.’s Keytruda has long been viewed as a standard of care in metastatic non-small cell lung cancer (NSCLC). Now, the PD-1 king has scored the FDA’s permission to enter early-stage disease with an approval that trumps Roche’s Tecentriq.
The FDA has cleared Keytruda for use after surgery and chemotherapy for early NSCLC across stages 1B, 2 or 3A, Merck said Friday. The approval covers patients regardless of their tumor’s PD-L1 expression levels.
Keytruda’s approval is bad news for Tecentriq, which scored the first nod for an immunotherapy in the postsurgery adjuvant NSCLC setting back in October 2021. Compared with Tecentriq’s green light for PD-L1-positive patients with stages 2 to 3A lung cancer, the Keytruda nod is broader in terms of both stage of cancer and PD-L1 status.
There are two small caveats in Keytruda’s new use, though. Like Tecentriq, Keytruda must be used following adjuvant chemotherapy. That's despite the fact that Merck’s supporting study for this use actually enrolled some patients who didn’t receive chemo. In that subgroup of patients, Keytruda takers somehow performed worse than those who didn’t get the drug, according to data from the phase 3 KEYNOTE-091 trial (PEARLS) presented at last year’s ASCO annual meeting.
In patients who received adjuvant chemo following surgery, Keytruda cut the risk of disease recurrence or death by 27% compared with placebo. Keytruda takers went a median 58.7 months without recurrence versus 34.9 months for the control group. The study covered stages 1B to 3A cases regardless of PD-L1 expression.
By comparison, in Tecentriq’s IMpower010 trial, the PD-L1 inhibitor cut the risk of recurrence or death by 34% in patients with PD-L-1-positive, stages 2 to 3A NSCLC.
As the second approval caveat, within stage 1B disease, the FDA only approved Keytruda in patients whose original tumors are at least four centimeters in size, even though the phase 3 trial also included smaller tumors.
But in handing Keytruda the broad adjuvant nod, the FDA looked past a relatively disappointing readout from the KEYNOTE-091 trial. In the PD-L1-high group with at least 50% expression, Keytruda posted a non-statistically significant 18% disease-free survival risk reduction at an interim analysis.
PD-1/L1 inhibitors are known to work better in PD-L1-high cases, so the poor showing in that subgroup in KEYNOTE-091 came as a surprise. Still, SVB Securities analyst Daina Graybosch, Ph.D., has argued that Keytruda will cross the statistical significance bar as the data mature.
The new nod makes Keytruda now the only cancer immunotherapy with FDA approvals in both adjuvant and metastatic NSCLC covering the entire PD-L1 expression spectrum.
While Keytruda and Tecentriq are slated to battle it out in adjuvant NSCLC, there remains an ongoing debate over whether PD-1/L1 inhibitors should be used before surgery as a neoadjuvant therapy rather than after surgery. Thanks to an FDA nod in March 2022, Bristol Myers Squibb’s Opdivo has already landed in the neoadjuvant setting.
Because neoadjuvant therapies are typically dosed for a shorter period than adjuvant drugs, Graybosch has warned that the entire PD-1/L1 class may have to live with smaller peak sales if doctors eventually lean toward neoadjuvant treatment.
Meanwhile, drugmakers appear to be pushing for a continuous neoadjuvant-plus-adjuvant regimen. Merck has a phase 3 trial dubbed KEYNOTE-671 exploring the neoadjuvant combination of Keytruda and chemo, followed by adjuvant Keytruda in stage 2 to 3b NSCLC. BMS has a similar study coded CheckMate-77T for Opdivo.