Two Practice-Changing Lung Cancer Trials Ignite Buzz

Standard-of-care chemotherapy regimens are becoming less attractive treatment strategies in the front-line setting of lung cancer as more immunotherapies and targeted therapies continue to be introduced and show better efficacy and safety. Multiple agents are now challenging chemotherapy as the golden standard in this setting.

Data from 2 clinical trials presented during the 2020 European Society of Medical Oncology (ESMO) Virtual Congress, especially, could change the way oncologists treat patients with lung cancers. The experimental arms each challenged standard-of-care chemotherapy and came out superior. Based on the data reported, there are promising new treatment option for patients with non–small cell lung cancer (NSCLC), in particular, for those with high PD-L1 expression in their tumors.

A Chemotherapy-Free Option for NSCLC With High PD-L1 Expression

The awaited 5-year follow-up data from the randomized, open-label, phase 3 KEYNOTE-024 clinical trial confirmed the benefit of pembrolizumab (Keytruda) as monotherapy compared with chemotherapy in patients with metastatic NSCLC who have a PD-L1 tumor proportion score (TPS) of at least 50%.¹

“What we have seen has been a consistent benefit in overall survival favoring those patients who have been treated with pembrolizumab. We’ve seen consistent benefit corresponding to a hazard ratio of 0.61,” Martin Reck, MD, PhD, head of the Clinical Trial Department at the Department of Thoracic Oncology at the Lung Clinic in Grosshansdorf, Germany, told Targeted Oncology in an interview.

The study included 305 patients who were randomized 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles or platinum-doublet chemotherapy for 4 to 6 cycles. The chemotherapy combinations used in the study were pemetrexed plus carboplatin, pemetrexed plus cisplatin, paclitaxel plus carboplatin, and gemcitabine plus cisplatin according to investigator discretion and histology. Patients in the pembrolizumab arm who completed 2 years of therapy or who stopped pembrolizumab after they achieved a complete response (CR) and then progressed, were able to have a second course of pembrolizumab for up to 17 cycles. Patients in the chemotherapy arm who had confirmed disease progression were eligible to cross over to pembrolizumab.

The primary end point of KEYNOTE-024 was progression-free survival (PFS) per RECIST v1.1, which was assessed by both blinded independent central review and investigator review. The key secondary end point was overall survival (OS). Other secondary end point assessed in the study included objective response rate (ORR), safety, and investigator-assessed PFS. Duration of response (DOR) was an exploratory end point in the trial.

As Reck explained, OS favored the pembrolizumab arm with a 26.3-month median OS (95% CI, 18.3-40.4) compared with the chemotherapy arm, which had a median OS of 13.4 months (95% CI, 9.4-18.3). Overall, the hazard ratio (HR) for the difference between these groups was 0.62 (range, 0.48-0.81).

The median PFS per investigator review was 7.7 months (95% CI, 6.1-10.2) in the pembrolizumab arm versus 5.5 months (95% CI, 4.2-6.2) in the chemotherapy arm. In total, this result represented 126 PFS event in the pembrolizumab group compared with 141 in the chemotherapy group (HR, 0.50; 95% CI, 0.39-0.65).

The ORR per investigator review was 46.1% for patients in the pembrolizumab arm compared with 31.3% for the chemotherapy arm. CRs were observed in 4.5% of the pembrolizumab group, but no patients treated with chemotherapy achieved a CR. Partial response (PRs) were observed in 41.6% of the pembrolizumab group versus 31.1% of the chemotherapy group. Additionally, 24.0% of the pembrolizumab arm had stable disease (SD) compared with 39.7% of the chemotherapy arm. Progressive disease (PD) was observed in 22.7% of the pembrolizumab arm compared with 16.6% of the chemotherapy arm.

The time to response on treatment was 2.1 months in both arms. The median DOR to pembrolizumab was much higher at 29.1 months (range, 2.2-60.8+) compared with 6.3 months (range, 3.1-52.4) to chemotherapy.

From the chemotherapy arm, 39 patients crossed over to pembrolizumab for 2 years of treatment. The 3-year OS rate observed in this group was 81%. On pembrolizumab, these patients achieved an ORR of 82% with CRs in 10%, PRs in 72%, and SD in 15%. Three percent of patients had PD. At data cutoff, 18 of the patients (47%) in this crossover group were still alive without PD.

The pembrolizumab-treated population who received a second course of treatment consisted of 12 patients. On their second course of pembrolizumab, the patients achieved an ORR of 33%, which were all PRs. Fifty percent of this population had SD while the remaining 8% had PD. Notably, at the time of data cutoff, 5 of the patients were alive without PD.

In terms of safety, treatment-related adverse events (TRAEs) was present in 76.6% of the pembrolizumab-treated population and 90.0% of the chemotherapy-treated population. TRAEs were grade 3 through 5 in 31.2% of patients treated with pembrolizumab versus 20.7% of those treated with chemotherapy. These TRAEs led to treatment discontinuation in 13.6% of the pembrolizumab group versus 10.7% of the chemotherapy group. Death occurred in 1.3% of the pembrolizumab group versus 2.0% of the chemotherapy group.

Immune-mediated AEs as well as infusion reactions were observed in 34.4% of the pembrolizumab arm versus in 5.3% of the chemotherapy arm. These events were grade 3 to 5 in 13.6% of the pembrolizumab-treated patients compared with 0.7% of the chemotherapy arm. No treatment discontinuation resulted from immune-mediated AEs or infusion reaction, but 1 death occurred in the pembrolizumab arm as a result.

The conclusion drawn from KEYNOTE-024 was that frontline immunotherapy with pembrolizumab monotherapy is an effective treatment for patients with metastatic NSCLC and a PD-L1 expression TPS ≥50%.

“With pembrolizumab monotherapy, we have introduced a new chemotherapy-free treatment opportunity for a group of patients with advanced non–small cell lung cancer and this is the group of patients with high PD-L1 expression on their tumor cells,” said Reck.

Reck also explained the importance of these data by making clear the characteristics of this patient population, saying “this subgroup is about 33% of our patients. It’s important to remember that these are patients without oncogenic alterations who have no targeted therapies available.”

Answers to Clinical Questions Around Anti–PD-1 Monotherapy in 1st-Line Advanced NSCLC

Treatment with cemiplimab-rwlc (Libtayo) demonstrated a significant improvement in both OS and PFS compared with chemotherapy in patients with advanced NSCLC and PD-L1 expression

≥50%, meeting the primary and secondary end points of the randomized, open-label, phase 3 EMPOWER-Lung 1 clinical trial.²

“These results support cemiplimab as a potential new option for anti–PD-1 monotherapy in first-line advanced non–small cell lung cancer,” Ahmet Sezer, MD, told Targeted Oncology.

Seven hundred ten patients were enrolled and randomized 1:1 to receive cemiplimab 350 mg every 3 weeks until PD or up to 108 weeks or 4 to 6 cycles of chemotherapy of the investigator’s choice. The chemotherapy agents used in the study included pemetrexed, paclitaxel, gemcitabine, cisplatin, and carboplatin. In the case of PD, patients in the cemiplimab arm were eligible to receive additional cemiplimab combined with 4 cycles of chemotherapy and those in the chemotherapy arm were eligible to cross over to cemiplimab.

In addition to the coprimary end points of OS and PFS, the secondary end points of the study included ORR, DOR, health-related quality of life (HR QoL), and safety.

The total number of patients treated was 355 out of 356 patients in the cemiplimab arm and 342 out of 356 in the chemotherapy arm. These patients were a part of the intention-to-treat population. After PD-L1 testing, the number of patients with high PD-L1 expression in their tumor cells who received cemiplimab was 283, and 280 received chemotherapy.

In patients with PD-L1 ≥50%, the median duration of follow-up was 10.8 months (range, 0.1-31.9) among those who received cemiplimab and 10.2 months (range, 0.2-29.5) among those who received chemotherapy. The median OS was not reached in the cemiplimab arm (95% CI, 17.9 to not evaluable [NE]) compared with 14.2 months (95% CI, 11.2-17.5) in the chemotherapy arm (HR, 0.57; 95% CI, 0.42-0.77; P = .0002). The 12-month OS rate observed with cemiplimab was 72.4% (95% CI, 65.6%-78.1%) versus 53.9% (95% CI, 46.2%-61.1%) in the chemotherapy arm. At 24 months, the OS rate was 50.4% (95% CI, 36.4%-62.9%) in the cemiplimab arm versus 27.1% (95% CI, 13.7%-42.5%) in the chemotherapy arm.

The median PFS observed with patients who had high PD-L1 was 8.2 months (95% CI, 6.1-8.8) in the cemiplimab arm compared with 5.7 months (95% CI, 4.5-6.2) in the chemotherapy arm (HR, 0.54; 95% CI, 0.43-0.68; P <.0001). At 12 months, the PFS rate in the cemiplimab arm versus the chemotherapy arm was 40.7% (95% CI, 33.7%-47.5%) versus 7.1% (95% CI, 3.6%-12.1%), respectively. At 18 months, the PFS rate in the cemiplimab arm was 27.8% (95% CI, 19.4%-36.7%) versus NE in the chemotherapy arm.

Tumor response in EMPOWER-Lung 1 also favored cemiplimab over chemotherapy. The ORR in the cemiplimab group was 39.2% (95% CI, 33.5%-45.2%) with CRs observed in 2.1% of patients. In comparison, the chemotherapy arm had an ORR of 20.4% (95% CI, 15.8%-25.6%) with PRs in 19.3% of patients and CRs in just 1.1%.

The median TTR was 2.1 months (range, 1.4-10.4) in the cemiplimab arm compared with 2.1 months (range, 1.4-6.3) in the chemotherapy arm. The median DOR was 16.7 months with cemiplimab (95% CI, 12.5-22.8) compared with 6.0 months (95% CI, 4.3-6.5) in the chemotherapy arm.

It was notable, according to Sezer, that tumor size decreased from baseline in the cemiplimab arm, and patients in the arm had better HR QoL outcomes compared with those who received chemotherapy.

Any-grade treatment-emergent AEs (TEAEs) were observed in 88.2% of patients in the cemiplimab arm versus 94.2% in the chemotherapy arm, which led to treatment discontinuation in 6.5% versus 4.1%, respectively. In terms of TRAEs, these impacted 57.5% of the cemiplimab arm versus 88.6% of the chemotherapy arm causing treatment discontinuations in 5.1% versus 3.5%, and death in 2.5% versus 2.0%, respectively.

Immune-mediated AEs occurred in 17.5% of the cemiplimab arm versus 2.3% of the chemotherapy arm. These events led to discontinuation of treatment in 2.5% of patients in the cemiplimab arm as well as death in 1 patient. No patients who received chemotherapy discontinued treatment or died from immune-mediated AEs.

The most common TEAEs observed in the study included anemia, decreased appetite, fatigue, and pneumonia.

Sezer told Targeted Oncology that “these data could address outstanding question for physicians in real-world clinical practices.”

_References:

_{1. Brahmer JR, Rodriguez-Abreu, Robinson AG, et al. KEYNOTE-024 5-year OS update: first-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumor proportion score (TPS) _50%. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA51.}

_{2. Sezer A, Kilickap S, Gumus M. et al. EMPOWER-Lung 1: Phase 3 first-line (1L) cemiplimab monotherapy vs platinum-doublet chemotherapy (chemo) in advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) _50%. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA52.}