Keytruda’s KEYNOTE-189 trial marked a watershed moment in the history of lung cancer drug development by showing a monster survival benefit. Now, Merck & Co. is giving a five-year look at the data that made the PD-1 inhibitor the standard of care in newly diagnosed patients.
After five years of Keytruda and chemotherapy, an estimated 19.4% of patients with newly diagnosed metastatic nonsquamous non-small cell lung cancer (NSCLC) were alive, versus 11.3% of those who received chemotherapy alone.
“Bear in mind that typically we’re thinking of five-year survival in this population of patients is on the order of around 5% from the era of just chemotherapy treatment,” Greg Lubiniecki, M.D., vice president of clinical research at Merck Research Laboratories, said in an interview ahead of a presentation of the updated KEYNOTE-189 data at the European Society of Medical Oncology (ESMO) annual meeting.
The five-year survival rate in KEYNOTE-189’s chemo control group appeared better than historical experience partly because the patients were allowed to receive Keytruda monotherapy after disease progression on their front-line treatment, Lubiniecki noted. But it’s still no match to the Keytruda-chemo combo group, which stressed the benefit of receiving Keytruda upfront in the first-line setting, he added.
Back in 2018, KEYNOTE-189 shook the cancer community by showing that the addition of Keytruda to chemo could cut the risk of death by 51%. Thanks to that huge showing—and trial setbacks by competitors—Keytruda quickly established itself as the standard of care in newly diagnosed NSCLC.
Now, after a median 64.6 months of follow-up, the risk reduction remained strong at 40%, as patients on Keytruda and chemo lived a median 22 months—more than double the median 10.6 months that the chemo group experienced.
At the ESMO 2022 meeting, Merck also provided a five-year update from the KEYNOTE-407 trial, which has been supporting Keytruda’s use alongside chemo in newly diagnosed squamous NSCLC.
Again, Keytruda nearly doubled the five-year survival rate. An estimated 18.4% of patients on the Keytruda-chemo regimen were alive after five years, compared with 9.7% in the chemo group. After a median follow-up of 56.9 months, Keytruda cut the risk of death by 29%, in line with the original analysis of 36%. Patients who took Keytruda and chemo lived a median 17.2 months, versus 11.6 months for those on chemo.
With the metastatic NSCLC market settled, Merck has shifted Keytruda’s focus to treatment of earlier-stage disease around surgery.
The New Jersey pharma also provided a PD-L1 subgroup analysis of the closely watched KEYNOTE-091 trial, which is testing postsurgery use of Keytruda in stages 1b to 3a NSCLC. As previously announced, Keytruda as an adjuvant therapy surprisingly only showed a nonsignificant 18% reduction in the risk of disease recurrence or death in patients with high PD-L1 expression covering at least 50% of tumor cells. Therefore, at the preplanned secondary interim analysis, the study has yet to hit the second of its dual primary endpoints.
Merck has attributed the lack of statistically significant benefit thus far to a better-than-expected performance from the placebo group and a smaller patient size for the PD-L1 subgroup.
According to data presented at the ESMO 2022 conference, Keytruda pared down the risk of event-free survival by 33% in patients with PD-L1 expression between 1% and 49% and by 22% in those with PD-L1-negative tumors.
The second interim analysis of KEYNOTE-091 happened after 117 patients in the PD-L1-high group had died. Lubiniecki declined to impart information on what would trigger another analysis or how many analyses remain. But he did say that the treatment effect of Keytruda in the postsurgery setting is consistent with the results with the drug in the metastatic setting, meaning patients with higher PD-L1 expression are deriving a greater treatment effect.
At this point, trial investigators estimate that about 65.9% of Keytruda takers with high PD-L1 expression will still be alive and disease-free after three years, versus 57.6% of those in the placebo group. The estimated rates are 54.6% for Keytruda takers with PD-L1 expression between 1% and 49% and 55.5% for PD-L1-negative patients who took Keytruda.
Thanks to a first-in-class nod in October 2021, Roche’s Tecentriq is the only PD-1/L1 inhibitor allowed in adjuvant NSCLC, but it’s limited to PD-L1-positive patients.