Chemotherapy plus pembrolizumab
Until recently, chemotherapy or immunotherapy alone had been standard first-line treatment for patients with advanced NSCLC without a targetable genetic alteration. Some studies suggest that many of the antitumor effects of chemotherapy are mediated through the immune system. Chemotherapy reduces T-regulatory cell activity and increases the ratio of cytotoxic T-lymphocytes to T-regulatory cells.19,20 Another study demonstrated that chemotherapy inhibits myeloid-derived suppressor cells.21 Cytotoxic chemotherapy also enhances presentation of tumor antigens as well as the potential for dendritic cell tumor antigen presentation following destruction of tumor cells.22,23 Further, PD-L1 expression on tumor cells can be upregulated by chemotherapy.24,25 Therefore, chemotherapy can act as a sensitizing agent to induce increased antitumor activity of PD-L1 and PD-1 antagonist antibodies. It is not clear if these immune based effects of chemotherapy drugs are clinically relevant or whether they significantly differ among different chemotherapeutic agents but formed the basis for evaluation of drugs targeting PD(L)-1 in combination with chemotherapy.
One of the first randomized studies to evaluate the combination of chemotherapy with a checkpoint inhibitor was Keynote 21G. In the Phase I portion of Keynote 21G toxicity and clinical activity of combination chemotherapy and immunotherapy were explored.26–29 The KEYNOTE-021 study demonstrated that addition of pembrolizumab to either carboplatin plus paclitaxel (cohort A); carboplatin, paclitaxel and bevacizumab (cohort B); or carboplatin plus pemetrexed (cohort C) had manageable safety profiles in cohorts A and C with the greatest antitumor activity in cohort C (75% ORR, PFS of 10.2 months; 95%CI: 6.5–13.9).27 Therefore, Langer et al30 sought to compare the efficacy and safety of pembrolizumab plus carboplatin and pemetrexed verus carboplatin and pemetrexed as first-line treatment in patients with advanced NSCLC with nonsquamous histology in the randomized Phase II study, Keynote 21G.
In this trial 123 patients were randomized (1:1), stratified by PD-L1 tumor proportion score (<1% or ≥1%) to receive either four cycles of pembrolizumab plus carboplatin and premetrexed followed by pemetrexed and pembrolizumab maintenance therapy for 24 months or four cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy. The primary endpoint was ORR with secondary endpoints of PFS, duration of response, OS and correlation between PD-L1 expression levels and antitumor activity. ORR was superior in patients treated with pembrolizumab plus carboplatin and pemetrexed (55%; 95%CI: 42–68) compared to chemotherapy alone (29%; 95%CI: 18–41). PFS was significantly longer with combination therapy compared to chemotherapy alone (HR: 0.53; 95%CI: 0.31–0.91). Median PFS was 13 months for combination therapy vs 8.9 months with chemotherapy alone with estimated 6 month PFS of 77% vs 63%. At the time of data cut-off no difference in OS was noted between treatment groups (HR: 0.90; 95%CI: 0.81–0.96) and 6-month survival was 92% in both treatment groups.30 Updated results from 24 months demonstrated a PFS of 24 months in patients treated with pembrolizumab plus chemotherapy vs 9.3 months for patients treated with chemotherapy alone (HR: 0.53; 95%CI: 0.33–0.86). The median OS was not reached in the pembrolizumab plus chemotherapy group while OS in the chemotherapy alone group was 21.1 months (HR: 0.56; 95%CI: 0.32–0.95).31 The most common treatment-related events were fatigue (64% in pembrolizumab + chemotherapy group vs 40% in chemotherapy alone group), nausea (58% vs 44%), and anemia (32% vs 53%). Patients treated with pembrolizumab plus chemotherapy had increased incidence of rash (27% vs 15%) and alopecia (14% vs 3%). Incidence of adverse events (AEs) based on presumed immunological mechanisms was 22% in the pembrolizumab plus chemotherapy group vs 11% in the chemotherapy alone group. However, the incidence of immune related AEs were no more than what would be expected with pembrolizumab alone. There was a low number of grade 3 skin reactions (2% in both groups) and grade 3 pneumonitis (2% in pembrolizumab plus chemotherapy group). The most common immune-mediated AEs of any grade in the pembrolizumab plus chemotherapy group were hypothyroidism (15%), hyperthyroidism (8%) and pneumonitis (5%). Given these results, carboplatin, pemetrexed, and pembrolizumab were granted accelerated FDA approval for patients with advanced, untreated, nonsquamous NSCLC.
More recently, in a Phase III, double-blind, placebo-controlled KEYNOTE-189 trial, Gandhi et al compared the combination of pembrolizumab or placebo plus pemetrexed and a platinum-based drug in patients with advanced, nonsquamous NSCLC with any level of PD-L1 level expression. The co-primary endpoints of the study were OS and PFS. Six hundred and sixteen patients with metastatic nonsquamous NSCLC who were treatment-naïve were randomized (2:1). At median follow-up (10.5 months) the estimated OS at 12 months was 69.2% (95%CI: 64.1–73.8) in the pembrolizumab-combination group, compared to 49.4% in the placebo combination. The median OS was not reached in the pembrolizumab-combination group and was 11.3 months in the placebo-combination group (HR: 0.49; 95%CI: 0.38–0.64; P<0.0001). The benefit of pembrolizumab combination was noted across all levels of tumor PD-L1 expression in patients (Table 1). Median PFS was 8.8 months in the pembrolizumab-combination group (95%CI: 7.6–9.2) while 4.9 months in the placebo-combination group (95%CI: 4.7–5.5) (HR: 0.52; 95%CI: 0.43–0.64; P<0.0001).32 OS and PFS outcomes did not change depending on platinum used. Adverse events of any cause occurred in 99.8% of the patients in pembrolizumab-combination group vs 99% of patients in the placebo-combination group. Grade 3 or higher events occurred in 67.2% vs 65.8% of patients, respectively. AEs led to 27 (6.7%) deaths in the pembrolizumab group vss 12 (5.9%) in placebo group. The most common adverse effects were nausea (55.6% vs 52.0%), anemia (46.2% vs 46.5%) and fatigue (40.7% vs 38.1%). Diarrhea and rash were reported more frequently in at least 10% of patients in the pembrolizumab group compared to the placebo group. Immune-mediated AEs occurred in 22.7% of patients treated with pembrolizumab combination vs 11.9% of patients treated with placebo combination. These events were grade 3 or higher in 8.9% vs 4.5%, respectively. AEs led to discontinuation of all trial drugs in 13.8% of patients in the pembrolizumab-combination group and 7.9% of patients in the placebo-combination group. Three immune-mediated AEs (pneumonitis) led to death in the pembrolizumab combination group. From these studies, it is now an accepted approach to treat patients with advanced, nonsquamous NSCLC with pemetrexed and a platinum-based drug plus pembrolizumab.
(To view a larger version of Table 1, click here.)
Recently, combination immunotherapy and chemotherapy has been studied in patients with advanced squamous NSCLC (Table 2). The Phase III KEYNOTE 407 trial randomized 559 patients with untreated metastatic squamous NSCLC in a 1:1 ratio to receive either pembrolizumab or saline placebo, plus carboplatin and either paclitaxel or nab-paclitaxel. At median follow-up of 7.8 months, PFS was 6.4 months in the pembrolizumab-combination group vs 4.8 months in the placebo-combination group (HR: 0.56; 95%CI: 0.45–0.70). OS was 15.9 months vs 11.3 months (HR: 0.64; 95%CI: 0.49–0.85) in patients treated with pembrolizumab plus chemotherapy vs placebo plus chemotherapy.33 PFS and OS outcomes did not change based on taxane used. This lead to FDA approval for pembrolizumab plus chemotherapy (carboplatin plus nab-paclitaxel or paclitaxel) in patients with advanced NSCLC with squamous histology.
(To view a larger version of Table 2, click here.)
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