Adding Keytruda to pre-surgical chemotherapy then giving it again after surgery improved event-free survival and pathologic complete response in patients with early-stage lung cancer.
Adding Keytruda (pembrolizumab) to pre-surgical chemotherapy and then again after surgery led to improvements in outcomes for patients with early-stage non-small cell lung cancer (NSCLC), according to findings from the phase 3 KEYNOTE-671 study presented at the 2023 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine.
In particular, this Keytruda regimen improved event-free survival, which is the time a patient lives without complications from the disease, as well as pathological complete response, which is when cancer is unable to be found on biopsy samples taken during surgery or after treatment.
In the double-blind study, the 24-month event-free survival rate was 62.4% with Keytruda plus chemotherapy and adjuvant Keytruda compared with 40.6% for placebo plus chemotherapy. The major pathologic response rate was 30.2% with Keytruda compared with 11.0% with placebo. The pathological complete response rate was 18.1% with Keytruda compared with 4.0% for placebo. Overall survival data were immature at the time of the analysis, with a 24-month overall survival rate of 80.9% observed in the Keytruda arm compared with 77.6% in the placebo arm.
“Neoadjuvant (Keytruda) plus chemotherapy followed by surgery and adjuvant (Keytruda) provided statistically significant, clinically meaningful improvement in (event-free survival) compared with neoadjuvant chemotherapy and surgery alone,” said lead investigator Dr. Heather Wakelee, from Stanford University School of Medicine and the Stanford Cancer Institute. “Data support perioperative (Keytruda) as a promising new treatment option for patients with resectable stage 2, 3A or 3B NSCLC.”
In the KEYNOTE-671 trial, patients were randomly assigned to receive chemotherapy plus Keytruda (397 patients) or placebo (399 patients). Keytruda was administered at 200 mg intravenously every three weeks in the neoadjuvant setting for four cycles and the adjuvant setting for 13 cycles. Chemotherapy was administered every three weeks and consisted of cisplatin plus either pemetrexed for nonsquamous histology or gemcitabine for those with squamous histology. Every three weeks, cisplatin was administered at 75 mg/m2, pemetrexed at 500 mg/m2, and gemcitabine at 1000 mg/m2 on days 1 and 8.
Baseline patient characteristics were balanced between groups. In the Keytruda group, the median age was 63 years, 70.3% were male, and the ECOG performance status was 0, meaning that there were little to no limitations to daily activities (63.7%) or 1 (36.3%). Two-thirds of patients were White (63%) and 31.2% were Asian, primarily from non-East Asian countries (69.0%). Histology was balanced at 56.9% nonsquamous and 43.1% squamous. A quarter of patients were current smokers (24.2%) and 13.6% were never smokers. The disease stage at baseline was most commonly 3A (54.7%) followed by stage 2 (29.7%), with the remainder being stage 3B (15.6%). Nearly half of patients had N2 disease (42.3%), with the remainder having N1 (20.4%) or N0 (37.3%).
PD-L1 status by tumor proportion score was balanced with a 33.2% having PD-L1 expression of 50% or greater and 34.8% having less than 1% expression of PD-L1. Those with known driver mutations were included in the trial, with 3.5% of tumors harboring an EGFR mutation and 3.0% with an ALK alteration. Driver mutation status was unknown for approximately two-thirds of patients.
Of the patents who entered the neoadjuvant phase, 87.4% completed three or more cycles of treatment in the Keytruda arm compared with 87.2% in the placebo group. There were 342 patients in the Keytruda arm who proceeded to surgery, compared with 335 in the placebo group, with 325 actually undergoing surgery in the Keytruda arm and 317 in the placebo group. Of those who underwent surgery, 290 received 1 or more doses of adjuvant therapy in the investigational arm compared with 267 in the placebo group. Slightly more than one third completed 13 cycles of adjuvant therapy in the Keytruda arm (40.4%) compared with 35.4% in the placebo group. Adjuvant therapy was ongoing for 10.6% and 11.3% of patients, in the investigational and control arms, respectively.
There were more complete R0 resections (complete remissions or cure) in the Keytruda arm compared with the placebo group, with 92.0% of patients receiving an R0 resection in the PD-1 inhibitor arm compared with 84.2% in the placebo group. Incomplete R1 resections occurred in 5.2% and 9.8% of patients in the Keytruda and placebo groups, respectively. The most common type of surgery was a lobectomy, which occurred in 78.8% of patients in the Keytruda arm and 75.1% in the placebo group.
The median follow-up at the July 29, 2022, data cutoff was 25.2 months. At this point, 35.0% of patients in the Keytruda arm had experienced an event, defined as local progression, progression, recurrence or death. In the placebo arm, 51.3% of patients had experienced an event. The median event-free survival was not yet reached with Keytruda compared with 17.0 months for the placebo group.
Event-free survival was consistently improved across subgroups, Wakelee noted, including those with driver mutations. She drew attention to a few key groups, noting that outcomes were similar by histology, PD-L1 expression level, and stage.
At the time of the data cutoff, 19.1% and 25.3% of patients had died from any cause in the Keytruda and placebo arms, respectively. The median overall survival was not yet reached for those in the Keytruda group compared with 45.5 months for the placebo group.
“The KEYNOTE-671 trial and other perioperative immunotherapy studies represent a major advance as new standards of care for the treatment of resectable lung cancer,” said ASCO discussant Dr.Mark M. Awad, from Harvard Medical School and the Dana-Farber Cancer Institute. “Although data are immature, there appears to be an encouraging signal for (overall survival) benefit favoring the neoadjuvant with or with adjuvant immunotherapy approach.”
“Neoadjuvant immunotherapy leads to high rates of mPR and pCR in a variety of solid tumors, and mPR and pCR after neoadjuvant immunotherapy are associated with excellent outcome,” said commenter Dr. Myriam Chalabi, from the Netherlands Cancer Institute. “De-escalation of systemic therapy, less extensive surgery, and omission of surgery are realistic options to consider.”
Treatment-related side effects were similar between treatment groups, with grade 3 to 5 events experienced by 44.9% of patients in the Keytruda group and 37.3% of those in the placebo group. Serious side effects were experienced by 17.7% and 14.3%, respectively. The most pronounced side effects differences were observed for immune-mediate side effects, including infusion reactions, Wakelee noted. Immune-mediate side effects occurred in 25.3% of patients treated with Keytruda compared with 10.5% in the placebo group. There was one death related to an immune-mediate side effect in the Keytruda arm. Immune-mediate side effects ed to Keytruda discontinuation for 5.1% of patients.
The most common side effects were those frequently associated with platinum-based chemotherapy, Wakelee said. These include nausea, neutropenia, anemia, leukopenia and fatigue. The most common all-grade, immune-mediate side effects for pembrolizumab and placebo, respectively, were hypothyroidism (11.1% vs 1.8%), hyperthyroidism (5.6% vs 3.3%), and pneumonitis (5.6% vs 1.8%).
“The (side effect) profile was as expected, based on the known profiles of the individual treatment components,” Wakelee said.
Merck, the developer of pembrolizumab, has already submitted a supplemental new drug application to the FDA, based on findings from the KEYNOTE-671 study. The proposed indication is for the treatment of patients with resectable stage 2, 3A or 3B NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment and continued as a single agent as adjuvant treatment. The FDA is expected to make a decision on the application by Oct. 16, 2023.
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