In a study reported at the European Society of Medical Oncology (ESMO) Virtual Congress 2020 ESMO Meeting, first-line cemiplimab monotherapy significantly improved overall survival (OS) and progression-free (PFS) vs platinum-doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) whose tumors express PD-L1 ≥50%. Despite a high crossover rate, the study provided a rationale for cemiplimab as a new treatment option for this patient population.
The EMPOWER-Lung 1 trial enrolled 712 patients with either locally advanced NSCLC (stage IIIB/C), who were not candidates for surgical resection or chemoradiation or who had progressed after treatment with chemoradiation. Patients with previously untreated metastatic NSCLC were also included.
Patients were randomized 1:1 to receive either 350 mg cemiplimuab-rwlc IV every 3 weeks for up to 108 weeks, or an investigator-selected, standard-of-care, platinum-based, doublet chemotherapy regimen for 4 to 6 cycles.
At median follow up of 13.1 months in the intent-to-treat (ITT) population, median OS was 22.1 months in the cemiplimab arm (95% CI, 17.7–not evaluable [NE]) vs 14.3 months (95% CI, 11.7–19.2) in the chemotherapy arm (n=354; HR, 0.68; 95% CI, 0.53–0.87; P=0.002). Median PFS was 6.2 months (95% CI, 4.5–8.3) with cemiplimab vs 5.6 months (95% CI, 4.5–6.1) with chemotherapy (HR, 0.59; 95% CI, 0.49–0.72; P<0.0001).
A prespecified analysis of data from patients whose cancers had confirmed PD-L1 expression ≥50% (n=563) was also conducted. In this group, the median follow-up was 11 months for both groups. Compared with chemotherapy, cemiplimuab-rwlc demonstrated a 43% reduced risk of death (HR, 0.57; 95% CI, 0.42-0.77; P =0.0002); the median OS was not yet reached (95% CI, 18 months to not yet evaluable) compared with 14 months (95% CI, 11-18 months) in the chemotherapy arm.
At 8.2 months, median PFS saw a 46% reduced risk of disease progression or death in the cemiplimuab-rwlc arm (HR=0.54; 95% CI, 0.43-0.68; P<0.0001) compared with 5.7 months (95% CI, 5-6) in the chemotherapy arm. Also observed in the ITT population was a 39% objective response rate (ORR) in the cemiplimab arm (95% CI, 34%-45%) vs 20% ORR in the chemotherapy arm (95% CI, 16%-26%).
The investigators concluded that in this study, first-line cemiplimab monotherapy significantly improved OS and PFS vs platinum-doublet chemotherapy in patients with advanced NSCLC expressing PD-L1 ≥50%.
In the KEYNOTE-024 study, which was first reported in 2016, 5-year results showed that first-line pembrolizumab continued to increase in overall survival (OS) vs chemotherapy in patients with metastatic PD-L1 expressed non-small cell lung cancer (NSCLC) with a tumor proportion score (TPS) ≥50%.
A total of 305 patients were randomized to pembrolizumab (200 mg every 3 weeks for up to 35 cycles [∼2 years]) or chemotherapy. Patients randomized to chemotherapy who expressed PD-L1 and met eligibility criteria were eligible to cross over to pembrolizumab monotherapy. Patients randomized to pembrolizumab who completed 2 years of therapy or who stopped pembrolizumab after achieving a complete response (CR) with PD-L1 expression were eligible for a second course of pembrolizumab monotherapy.
Despite the high crossover rate, the 5-year overall survival was approximately doubled among patients who received pembrolizumab (31.9% vs 16.3%). Fewer patients who received pembrolizumab experienced grade 3−5 adverse events vs those who received chemotherapy. Long-term overall survival and durable responses were observed with pembrolizumab monotherapy.
Commenting on the study, Julie Brahmer, MD, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, said, “this was one of the first phase 3 studies that have demonstrated an overall 5-year survival advantage, when being treated with single agent pembrolizumab. Again, this was a population that had high PD-L1 or a tumor proportion score of 50% or more. I'm happy to see the 5-year overall survival rate improve and I’m hoping that we can say now that we can cure some of our patients with metastatic disease, but we have a long way to go for the majority of the patients.”
Compared with crizotinib, lorlatinib resulted in a statistically significant improvement in progression-free survival (PFS) in patients with advanced ALK-positive non-small cell lung cancer (NSCLC). The results were reported at ESMO by Benjamin Solomon MD, Melbourne, Australia.
Treatment-naïve patients with ALK-positive stage IIIB/IV NSCLC were randomized 1:1 to oral lorlatinib (100 mg QD) or crizotinib (250 mg BID); stratified by presence of CNS metastases and ethnicity. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). This was a planned interim analysis conducted at 72% of 177 expected PFS events.
Of 296 patients enrolled, 291 received study treatment. As of March 2020, the median follow-up for PFS by BICR was 18.3 months (95% CI, 16.4–20.1) for lorlatinib (n=149) and 14.8 months (95% CI, 12.8–18.4) for crizotinib (n=147). The PFS by BICR was significantly prolonged with lorlatinib vs crizotinib (HR, 0.28; 95% CI, 0.191–0.413; stratified one-sided P<0.001). The lorlatinib median PFS was not estimable) vs crizotinib at 9.3 months (95% CI, 7.6–11.1).
More grade 3 or 4 adverse events were reported in the lorlatinib group than in the crizotinib group (72 vs 56%), which according to Dr. Solomon were mainly laboratory abnormalities (hypercholesterolemia and hypertriglyceridemia).
“The study met its primary endpoint. It was strongly positive with a hazard ratio of 2.8 which is highly significant. This translated into a 72% risk of death or progression with lorlatinib treatment. The study was also significant in showing an improvement of the overall response rate of 76% compared to 58%,” Dr. Solomon said.
“The results of this phase III CROWN study resulted in lorlatinib as a highly effective option for first-line treatment of ALK-positive NSCLC,” he said.
For patients with advanced epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC), amivantamab can be combined safely with lazertinib at their full monotherapy doses. The primary objective of the CHRYSALIS study was to establish a recommended phase II dose of amivantamab and to evaluate safety and efficacy of the combination.
Patients (n=91) with EGFR exon 19 deletion or L858R mutation non-small cell lung cancer (NSCLC) were enrolled in this two-part study. To identify the recommended phase 2 combination dose, Part 1 enrolled patients without restriction on prior therapy to evaluate escalating dose cohorts of amivantamab (700–1050 mg, IV once weekly for 28 days; biweekly thereafter) in combination with standard monotherapy dosing of lazertinib (240 mg oral daily).
According to Dr. Cho, 20 patients with treatment-naïve disease were enrolled in the study. The overall response rate (ORR) was 100%, which he described as “deep and durable.” The clinical benefit rate was also 100%. The response was rapid. In chemotherapy-naïve patients the ORR was 36% and the clinical benefit rate was 60%. “Although the follow up was short, the ORR and clinical benefit rates were very promising,” he said.
The ORR to cytotoxic chemotherapy is usually 3 to 4 months and 10% to 15%, respectively. “These are patients who progressed on lazertinib. They have a very poor prognosis and I think this combination may be a hope in the near future when they complete a global phase 3 study,” Dr. Cho said.
Additionally, 45 osimertinib-relapsed patients received the combination therapy which saw a 36% ORR. According to Byoung Chul Cho, MD, PhD, Yonsei Cancer Center, Seoul, Korea, this shows encouraging preliminary activity. The preliminary results of the CHRYSALIS phase I study were reported at the European Society of Medical Oncology (ESMO) 2020 Virtual Meeting.