One outstanding question that remains to be answered is whether patients treated with pembrolizumab-combination have better survival compared to patients treated with pembrolizumab monotherapy, in those patients with ≥50% PD-L1 tumor expression. In a subset analysis of KEYNOTE 189 based on PD-L1 expression, survival benefit with chemotherapy and pembrolizumab was greater in patients with tumor PD-L1 expression ≥50% (HR: 0.42) than in patients with lower PD-L1 expression (HR: 0.55) or no PD-L1 expression (HR: 0.59). In addition, this survival benefit among patients with tumor PD-L1 expression of ≥50% appears to be greater than the survival benefit with pembrolizumab alone compared to chemotherapy in KEYNOTE 024 (HR: 0.60) and KEYNOTE 042 (HR: 0.69). Similar differential efficacy of the combination of pembrolizumab with chemotherapy was not observed in KEYNOTE 407 conducted in squamous cell patients and the survival benefit in patients with tumor PD-L1 expression ≥50% (HR: 0.64) in this study does not appear to be better than pembrolizumab alone. Thus, it is possible that in patients with nonsquamous NSCLC, combination pembrolizumab with chemotherapy may provide an added survival benefit in patients with tumor PD-L1 expression ≥50% than pembrolizumab alone, however, this benefit may not necessarily be observed in squamous cell patients. Such inferences based on across-trial comparisons should be viewed with a high level of caution. Studies specifically assessing the role of combination chemotherapy in addition to pembrolizumab in patients with tumor PD-L1 expression ≥50% are warranted.

It will also be important to understand if TMB plays a role in helping to determine which patients with advanced, nonsquamous NSCLC will respond more robustly to pembrolizumab-combination treatment. Altogether, chemotherapy plus pembrolizumab appears to be more efficacious than chemotherapy alone in patients with advanced, nonsquamous NSCLC.

Chemotherapy + immunotherapy (other combinations)

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Other combinations of chemotherapy and immunotherapy agents have recently been studied in patients with advanced NSCLC (Table 1). The IMpower150 trial randomized 1,202 patients irrespective of PD-L1 status with advanced, nonsquamous NSCLC to first-line carboplatin and paclitaxel every 3 weeks combined with either atezolizumab (1,200 mg IV every 3 weeks), atezolizumab plus bevacizumab or bevacizumab alone. Primary endpoints were PFS and OS and compared atezolizumab, bevacizumab, carboplatin, paclitaxel vs bevacizumab, carboplatin, paclitaxel. PFS was noted to be improved in patients treated with the atezolizumab combination as compared to non-atezolizumab combination (8.3 months vs 6.8 months; HR for disease progression or death: 0.62; 95%CI: 0.52–0.74). Interim analysis of OS was 19.2 months in patients treated with the atezolizumab combination compared to 14.7 months with non-atezolizumab combination (HR due death: 0.78; 95%CI: 0.64–0.96). Overall survival was also measured in patients treated with atezolizumab plus carboplatin and paclitaxel vs carboplatin, paclitaxel and bevacizumab and no significant difference was observed (HR: 0.88; 95%CI: 0.72–1.08). It should be noted that this trial enrolled patients with EGFR or ALK positive NSCLC (who had received at least one line of targeted therapy) and in subgroup analysis OS and PFS was noted to benefit these patients treated with the atezolizumab combination compared to the non-atezolizumab combination.34 Recently the FDA approved the carboplatin, paclitaxel, bevacizumab and atezolizumab as front-line therapy for nonsquamous NSCLC patients without EGFR or ALK genetic alterations.

The IMpower132 study also assessed atezolizumab plus combination chemotherapy combination. This was a Phase III randomized trial of patients with advanced, nonsquamous NSCLC. Patients were randomized to either atezolizumab plus pemetrexed and platinum-based chemotherapy (cisplatin or carboplatin) or chemotherapy alone. Interim analysis demonstrated increased PFS with atezolizumab combination vs chemotherapy alone, 7.6 vs 5.2 months (HR: 0.60; 95%CI: 0.49–0.72). OS was also improved, 18.1 vs 13.6 months (HR: 0.81; 95%CI: 0.64–1.03) however, this was not significant at interim analysis.35 It should be noted that these results appear to be similar to the results observed in KEYNOTE-189.

Treatment with atezolizumab plus chemotherapy has also been evaluated in patients with squamous NSCLC (Table 2). The IMpower131 trial is a randomized Phase III trial which enrolled patients with advanced squamous cell lung cancer. Patients received either atezolizumab plus carboplatin and paclitaxel or nab-paclitaxel vs chemotherapy (carboplatin and nab-paclitaxel). Interim analysis demonstrated improved PFS of 6.3 months vs 5.6 months in patients treated with atezolizumab plus carboplatin and nab-paclitaxel vs chemotherapy alone (HR: 0.715; 95%CI: 0.603–0.848).36 PFS benefit was irrespective of PD-L1 status. However, a statistically significant OS benefit was not observed at interim analysis.

Nivolumab has also been studied in combination with chemotherapy in patients with advanced NSCLC. The Phase I CheckMate 012 trial enrolled patients with Stage IIIb and IV, chemotherapy-naïve NSCLC and randomized patients to nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks, or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicities or withdrawl of consent. The study demonstratd that nivolumab plus ipilimumab had a tolerable safety profile and demonstrated a confirmed ORR of approximately 47% (95%CI: 31–64) in patients treated with 12 week ipilimumab and 38% (95%CI: 23–55) in patients treated with 6-week ipilimumab.37

More recently, results from the CheckMate 568 trial were published. This Phase II trial evaluated the efficacy and safety of nivolumab 3 mg/kg every 2 weeks plus low-dose ipilimumab (1 mg/kg every 6 weeks) in patients with advanced or metastatic NSCLC. Primary end point was ORR in patients with 1% or more and less than 1% PD-L1 expression. Efficacy on the basis of TMB was also assessed as a secondary endpoint. ORR was 41% in patients with 1% or more PD-L1 expression and 15% in patients with less than 1% expression. Patients with TMB of 10 or more mutations/megabase portended a higher ORR, 48% vs patients with less than 10 mutations/megabase, 18%. PFS was also longer in patients with high TMB (10 or more mutations/megabase) vs lower TMB (fewer than 10 mutations/Mb), 7.1 (95%CI: 3.6–11.3) vs 2.6 months (95%CI: 1.4–5.4).38

The CheckMate 227 trial randomized patients with advanced, untreated NSCLC to histology-matched, platinum doublet chemotherapy, nivolumab plus ipilimumab or either nivolumab alone in patients with tumor PD-L1 expression ≥1% or nivolumab plus chemotherapy in patients with tumor PD-L1 expression ≤1% (Table 3). Across all the arms, 1,739 patients were enrolled on the trial. One of the co-primary end points of the study was to assess PFS based on TMB. In this trial TMB was determined using the Foundation CDx assay. Previous studies utilizing whole exome sequencing had demonstrated significant clinical benefit with PD-1/PD-L1 inhibitors in patients with high TMB. The results of the first part of the study comparing nivolumab plus ipilimumab to chemotherapy in patients with high TMB (≥10 mutations per megabase) demonstrated increased PFS with nivolumab plus ipilimumab as compared to chemotherapy (7.2 months vs 5.4 months, HR for disease progression or death: 0.58; 97.5%CI: 0.41–0.81). Of the 679 evaluable patients, 44% (299 patients) had high TMB. It was also noted in the study that outcomes were irrespective of PD-L1 tumor expression status. ORR in patients with high TMB was also higher with nivolumab plus ipilimumab (45.3% vs 26.9%).39 Further preliminary results from CheckMate 227 assessing nivolumab and chemotherapy compared to chemotherapy alone in patients with tumor PD-L1≤1% demonstrated improved PFS with combination nivolumab and chemotherapy (5.6 months vs 4.7 months; HRL 0.74l 95%CI: 0.58–0.94). In subgroup analysis patients receiving nivolumab plus chemotherapy combination therapy who had high TMB tumors derived benefit while those with low TMB tumors did not.40 Survival advantage has not yet been demonstrated in any of the treatment arms. These studies suggest that TMB may be a biomarker predictive of benefit from nivolumab combinations both with ipilimumab and with chemotherapy. In the future it will be important to understand how both tumor TMB and PD-L1 expression can be used to make treatment decisions.

(To view a larger version of Table 3, click here.)

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