TORONTO — Patients with inoperable lung cancer lived without metastasis more than twice as long as expected when they received consolidation immunotherapy with pembrolizumab (Keytruda) after standard chemoradiation therapy (CRT), a phase II clinical study showed.
The median time to metastatic disease or death (TMDD) had yet to be reached after about 2 years of follow-up, but the estimated median was 30.7 months. Investigators hypothesized that the median TMDD would increase from 12 months with chemoradiation (CRT) alone to 18 months with chemoradiation followed by consolidation.
The median TMDD exceeded the 23.2-month median observed in the recent randomized PACIFIC trial of durvalumab (Imfinzi), and the median progression-free survival (PFS) was similar in the two trials. The 24-month overall survival exceeded 60%, reported Greg Durm, MD, of the Simon Cancer Center at Indiana University in Indianapolis, at the World Conference on Lung Cancer (WCLC) here.
“Consolidation with PD-1/PD-L1 inhibition is relatively safe and should be considered a new standard of care for unresectable stage III NSCLC (non-small cell lung cancer),” said Durm. “With longer follow-up, both TMDD and PFS continue to be considerably improved over historical controls. Compared with historical controls, our data suggest a significant increase in overall survival [OS] for this patient population.”
The trial confirmed that consolidation therapy following concurrent CRT is safe and feasible in a majority of patients with inoperable stage III NSCLC, said WCLC invited discussant Corey Langer, MD, of the University of Pennsylvania in Philadelphia.
“Consolidation pembrolizumab following concurrent CRT substantially improves TMDD and PFS compared to historical controls,” said Langer. “The preliminary overall survival data are very promising and suggest a major improvement in survival for this patient population.”
However, Langer cited several concerns/questions about the study: fewer than half of the 93 patients completed the planned 1 year of treatment; the relationship between outcomes and PD-L1 status and duration of consolidation treatment remain unclear; potential late effects of treatment on normal tissues are unknown.
Patients with unresectable stage III NSCLC have a poor prognosis, associated with a 5-year survival of 15%-20% for patients with stage IIIa disease and 5%-10% for stage IIIb disease, Durm noted. Concurrent CRT has represented standard of care for almost 2 decades.
Interest in immunotherapeutic approaches to consolidation therapy followed recent evidence that radiation might have a “priming” effect that includes upregulation of PD-L1 on tumor cells, recruitment of T-cells to the tumor bed, and neutralization of immunosuppressive effects within the tumor microenvironment. Preclinical data suggested that PD-1/PD-L1 inhibition might have synergistic activity with radiation, Durm continued.
The PACIFIC trial provided the strongest evidence to date in support of consolidation immunotherapy for inoperable stage III NSCLC. Patients who received durvalumab after conventional CRT had a median PFS of 16.8 months versus 5.6 months for those who received CRT alone. OS from the trial will be reported Tuesday during a WCLC plenary session.
Durm reported findings from a single-arm, multicenter phase II trial to evaluate pembrolizumab consolidation after CRT in 93 patients with unresected stage III NSCLC. Patients received one of three chemotherapy regimens: cisplatin plus etoposide, carboplatin plus paclitaxel, or cisplatin plus pemetrexed (Alimta). Chemotherapy was administered concurrently with radiation therapy (total dose of 59.4-66.6 Gy).
Patients who had stable disease or objective response to CRT received consolidation therapy with pembrolizumab, administered every 3 weeks for as long as a year. Patients who had progressive disease after CRT were ineligible for consolidation treatment with pembrolizumab.
The study population consisted of 59 men and 33 women, 95% of whom were former (77.2%) for current (17.4%) smokers. About 60% of the patients had stage IIIa disease. Among 54 patients with known PD-L1 expression status, 11 tested negative, 11 exhibited 1-49% expression, and 31 had expression values of 50-100%.
The most common adverse event (all grades) was fatigue (47.3%), followed by cough (25.8%), and dyspnea (21.5%). The most common grade 3 adverse events were dyspnea (5.4%), fatigue (4.3%), and diarrhea (4.3%). No grade 4-5 adverse events occurred.
Durm said 17.2% of patients developed the immune-related adverse event pneumonitis, consisting of 10.8% grade 2, 4.3% grade 3, and 1.1% each for grade 4 and grade 5. The median interval to grade ≥2 pneumonitis was 8.4 weeks, and in three-fourths of cases, pneumonitis occurred within the first 12 weeks of pembrolizumab treatment.
In addition to the 30.7-month median TMDD, the results showed TMDD of 76.34% at 12 months, 60.0% at 18 months, and 52.3% at 24 months. The median PFS was 15.0 months, including 60.8% at 12 months, 46.9% at 18 months, and 41.4% at 24 months. Median OS had yet to be reached. The 12-month, 18-month, and 24-month survival rates were 81.3%, 65.3%, and 61.5%, respectively.
Durm disclosed relevant relationships with Merck, Bristol-Myers Squibb, and AstraZeneca.