First-line treatment with immunotherapy in metastatic squamous NSCLC
Immunotherapy has dramatically changed the therapeutic scenario in the treatment-naïve advanced NSCLC. While the single agent pembrolizumab has become the standard first-line therapy in patients with ≥50% PD-L1 expression on tumor cells, the combination of pembrolizumab and chemotherapy has emerged as an effective first-line treatment regardless of PD-L1 expression in squamous NSCLC.1,2 Furthermore, the combination of pembrolizumab and chemotherapy has shown comparable survival benefit in the Chinese population.3 In a recent symposium, Professor Luis Paz-Ares, Head of Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain discussed first-line immunotherapy treatment in NSCLC and management of lung cancer patients in the era of COVID-19 pandemic.
Single agent immunotherapy with pembrolizumab improved survival benefit in NSCLC patients
Pembrolizumab, a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, is approved as a single agent for the first-line treatment of metastatic NSCLC with PD-L1 TPS ≥1%, and in combination with chemotherapy for metastatic squamous and non-squamous NSCLC irrespective of PD-L1 expression.4 Previously in the non-randomized phase I KETNOTE-001 trial, patients receiving single-agent pembrolizumab had a median OS of 12.0 months.5 In treatment-naïve NSCLC patients, a 5 year OS of 23.2% was observed.6 Subsequent confirmatory open-label phase 3 KEYNOTE-024 trial, pembrolizumab monotherapy was compared to platinum-based chemotherapy in treatment-naïve patients with advanced NSCLC whose tumors express a PD-L1 TPS ≥50%.7 Pembrolizumab was associated with significantly longer progression free survival (PFS) and overall survival (OS) with fewer adverse events than platinum-based chemotherapy.7 A similar OS benefit was also observed between non-squamous and squamous NSCLC patients.7 Prof. Paz-Ares stated, “Due to these data, pembrolizumab monotherapy is considered as standard of care in first-line treatment for metastatic NSCLC with high PD-L1 expression (TPS ≥50%).”
KEYNOTE-407: Combination of pembrolizumab and chemotherapy is effective regardless of PD-L1 expression
The double-blind, placebo-controlled, phase 3 KEYNOTE-407 trial randomized patients with stage IV untreated squamous NSCLC to receive either carboplatin plus paclitaxel or nab-paclitaxel plus pembrolizumab, or placebo.8 The primary endpoints were PFS and OS, and the patients were stratified according to PD-L1 expression (TPS <1% or ≥1%) and the choice of taxane (paclitaxel vs. nab-paclitaxel).8 After a median follow-up of 7.8 months, adding pembrolizumab to standard chemotherapy significantly improved OS over chemotherapy alone: median OS was 15.9 vs. 11.3 months (Hazard ratio (HR) for death=0.64, 95% CI: 0.49-0.85) despite a cross over rate of 31.7%.8 This survival benefit was evident in all the subgroups regardless of PD-L1 expression levels.8 PFS was also improved with pembrolizumab over chemotherapy alone with a median PFS of 6.4 versus 4.8 months (HR for disease progression or death=0.56, 95% CI: 0.45-0.70) with the objective response rate (ORR) almost doubled (58% vs. 38%).8 Pembrolizumab plus chemotherapy showed a safety profile where the frequency and severity of toxicities were similar to chemotherapy alone, with grade 3–5 adverse events occurred in 69.8% of patients in the combination arm vs. 68.2% in the chemotherapy alone arm.8
In addition to OS and PFS, an exploratory primary endpoint PFS-2 explored the time from randomization to progression on next-line treatment/death, whichever occurred first.9 At a median follow-up of 14.3 months in the protocol-specified final analysis, pembrolizumab plus chemotherapy continued to demonstrate a clinically meaningful improvement over placebo plus chemotherapy in OS at 17.1 vs. 11.6 months (HR=0.71; 95% CI: 0.58‒0.88) (Figure 1).9 PFS-2 was longer for patients randomized to first-line pembrolizumab plus chemotherapy than placebo at 13.8 vs. 9.1 months (HR=0.59; 95% CI: 0.49-0.72).9 These results supported pembrolizumab plus chemotherapy as a standard first-line treatment in patients with metastatic squamous NSCLC.9
Most importantly, the addition of pembrolizumab to chemotherapy maintained or improved health related quality of life (HRQoL) measurements relative to baseline and versus chemotherapy alone at weeks 9 and 18.10 In light of these findings, Prof. Paz-Ares emphasized, “These results support the use of pembrolizumab plus chemotherapy as first-line therapy for metastatic squamous NSCLC regardless of PD-L1 expression levels”.
KEYNOTE-407 China extension study shows consistent outcomes with global study
The China extension study was designed similar to the global study.3 Total 125 patients were enrolled. After a median follow-up of 10.4 months, the results showed that the pembrolizumab group had a longer median OS at 17.3 months versus 12.6 months in the control group, indicating that pembrolizumab combined with carboplatin plus paclitaxel reduced mortality by 56% (HR=0.44; 95% CI: 0.24‒0.81) (Figure 2). Median PFS were 8.3 months in the combination arm and 4.2 months in the control arm, indicating that pembrolizumab combined with carboplatin plus paclitaxel reduced the risk of progression or mortality by 68% (HR=0.32; 95% CI: 0.21‒0.49) when compared to control.3
Moreover, pembrolizumab combined with carboplatin plus paclitaxel improved ORR by 36.8% (78.5% vs. 41.7%). Duration of response (DOR) has also improved with the combination of pembrolizumab by 5.4 months.3 The rates of grade 3-5 AEs were similar between the two groups at 89% and 87% in the pembrolizumab plus chemotherapy and placebo plus chemotherapy arms, respectively.3 “The results of the KEYNOTE-407 China extension study are consistent with those of the global KEYNOTE-407 study,” remarked Prof. Paz-Ares.
Understanding lung cancer patients infected by SARS-CoV-2
At the latter part of the symposium, Prof. Paz Ares shared the effects of COVID-19 pandemic on the lung cancer patients by highlighting that “presence of lung cancer or lung metastasis has been shown to correlate with the mortality among cancer patients with COVID-19.” In a cohort study that recruited COVID-19 patients with active or prior hematologic or invasive solid malignancies, all-cause 30-day mortality was found to be significantly associated with the general factors of increasing age, male sex, former smoking, number of comorbidities, and receipt of azithromycin plus hydroxychloroquine; cancer-specific factors of moderate or poor Eastern Cooperative Oncology Group performance status and active (measurable) cancer were also found to be associated with all-cause 30-day mortality. However, as cancer type and treatment were not independently associated with increased 30-day mortality, it is crucial to understand the impact of COVID-19 on patients with lung cancer to ensure optimal care.11
The TERAVOLT is the first global registry aimed at understanding the effect of SARS-CoV-2 infection on patients with thoracic malignancies.12 Among the 428 patients studied in TERAVOLT, the median age was 67.0, 70.0 and 66.5 years in the recovered (n=169), died (n=141), and ongoing hospitalization group (n=118), respectively. A majority of patients were male and were current or former smokers. Notably, the most common histology was NSCLC followed by small-cell lung cancer with most patients having stage IV disease.12 Many patients were being treated with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and have received 1 line of cancer therapy in the last 3 months with the most common comorbidities being hypertension and COPD.12
The most common presenting symptoms were fever, dyspnea, and cough. Out of the 428 patients studied, 59%, 71% and 33% had developed pneumonia or pneumonitis in the recovered, died, and ongoing hospitalization group, respectively. Notably, patients that have died have a much higher proportion of developing acute respiratory distress syndrome at 49.6% vs. the recovered and ongoing hospitalization group at 4.1% and 11.9%, respectively.12 Interestingly, among the 400 patients that were under ongoing hospitalization or had previous hospital admissions from the recovered or died group, only 8.3% were admitted to the intensive care unit and only 5.0% were mechanically ventilated.12 A total of 141 (35.5%) patients have died, with 112 (79.4%) patients died due to COVID-19 only, 15 (10.6%) patients died due to cancer only, 12 (8.5%) patients died due to cancer and COVID-19 together.12
Multivariate analysis revealed that age older than 65 years and having an Eastern Cooperative Oncology Group (ECOG) Performance Status score =1 was associated with an increased risk of death at a hazard ratio of 1.70 and 2.14, respectively. Most importantly, patients with prior administration of chemotherapy were associated with an increased risk of death when compared to no treatment and immunotherapy or targeted therapy at a hazard ratio of 1.71 and 1.64, respectively.12 This result indicated that immunotherapy or targeted therapy were not associated with an increased risk of death in cancer patients with COVID-19.12
In summary, older age, being a current or former smoker, receiving treatment with chemotherapy alone, and the presence of any comorbidities were associated with an increased risk of death in patients with thoracic malignancies under the COVID-19 pandemic.
Pembrolizumab monotherapy has become the standard first-line therapy for metastatic NSCLC patients with ≥50% PD-L1 expression on tumor (TPS ≥50%) without EGFR or ALK aberrations. Additionally, pembrolizumab combined with chemotherapy significantly improved the OS, PFS, ORR for patients with squamous metastatic NSCLC. This regimen is well tolerated by these patients. Therefore, combination therapy of pembrolizumab and chemotherapy is preferred over chemotherapy alone regardless of PD-L1 expression. For the Chinese population, first-line treatment with pembrolizumab combined with chemotherapy also significantly improved the survival benefits. Pembrolizumab has broadly revolutionized the first-line treatment of advanced NSCLC patients with no oncogenic drivers.
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