The use of immunotherapy, either as monotherapy or in combination with chemotherapy, continues to raise the bar with regard to overall survival benefit in patients with newly diagnosed, advanced nonsquamous non–small cell lung cancer.
Jamie E. Chaft, MD
The use of immunotherapy, either as monotherapy or in combination with chemotherapy, continues to raise the bar with regard to overall survival (OS) benefit in patients with newly diagnosed, advanced nonsquamous non—small cell lung cancer (NSCLC), said Jamie E. Chaft, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center.
“We’re seeing some truly durable, if not curable responses,” said Chaft in a presentation during the 2019 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer.
Such responses can be traced back to the phase III KEYNOTE-024 trial,1 which compared the use of pembrolizumab (Keytruda) monotherapy with investigator’s choice of platinum-based chemotherapy in patients with newly diagnosed advanced nonsquamous (n = 249) or squamous (n = 56) NSCLC and a PD-L1 tumor proportion score (TPS) of ≥50%.
Results showed a 40% reduction in the risk of death in the overall population (HR, 0.60; 95% CI, 0.41-0.89; P = .005). Data from the trial served as the basis for the October 2016 approval of pembrolizumab as frontline therapy in patients with metastatic disease whose tumors have ≥50% PD-L1 expression and who do not harbor EGFR or ALK alterations. With prolonged follow-up, frontline pembrolizumab monotherapy continued to demonstrate an OS benefit over chemotherapy with a median OS of 30.0 months for pembrolizumab versus 14.2 months with chemotherapy (HR, 0.63; 95% CI, 0.47-0.86).2
To broaden understanding of the benefit seen with single-agent pembrolizumab, investigators launched the phase III KEYNOTE-042 trial,3 which again, compared pembrolizumab monotherapy with platinum-based chemotherapy, but in patients with a PD-L1 TPS of ≥50%, ≥20%, and ≥1%.
Pembrolizumab monotherapy led to a significantly longer survival benefit than chemotherapy, and that benefit was seen across all 3 TPS populations: ≥50% (HR, 0.69; 95% CI, 0.56-0.85; P = .0003), ≥20% (HR, 0.77; 95% CI, 0.64-0.92; P = .0020), and ≥1% (HR, 0.81; 95% CI, 0.71-0.93; P = .0018). Although the monotherapy was approved for patients with a PD-L1 TPS of ≥1% in April 2019, its benefit is largely driven by patients with PD-L1 ≥50%, according to Chaft.
As a next step for pembrolizumab, investigators launched the phase KEYNOTE-189 trial,4 in which patients with previously untreated disease were randomized to receive either the PD-1 inhibitor in combination with platinum-based chemotherapy or placebo plus platinum-based chemotherapy.
Results showed a dramatic improvement in OS, said Chaft. At a median follow-up of 10.5 months, the estimated 12-month OS rate was 69.2% in the chemoimmunotherapy arm versus 49.4% in the chemotherapy/placebo arm (HR, 0.49; 95% CI, 0.38-0.64; P <.001). As in the KEYNOTE-042 trial, patients with PD-L1 TPS ≥50% derived the most benefit from the addition of pembrolizumab (HR, 0.42; 95% CI, 0.26-0.68) versus those with PD-L1 TPS 1% to 49% (HR, 0.55; 95% CI, 0.34-0.90) and PD-L1 TPS <1% (HR, 0.59; 95% CI, 0.38-0.92). The frontline combination was granted a full approval for all patients with metastatic nonsquamous NSCLC in August 2018. At 18.7 months of median follow-up, pembrolizumab plus chemotherapy continued to provide longer OS than placebo plus chemotherapy (HR, 0.56; 95% CI, 0.45-0.70; P <.00001) across all PD-L1 TPS groups.5
“[The combination of pembrolizumab and chemotherapy is what] most clinicians are leaning toward in patients who are not amenable or eligible for monotherapy with pembrolizumab,” said Chaft.
To determine eligibility for either approach, PD-L1 testing, preferably with the PD-L1 IHC 22C3 pharmDx assay should be performed, as a TPS ≥50% could indicate that the patient is best suited to receive single-agent pembrolizumab, said Chaft. Although PD-L1 expression is useful in such scenarios, it should not be heralded as a definitive biomarker, she added.
Atezolizumab (Tecentriq) has also been evaluated in combination with chemotherapy. In the phase III IMpower150 trial,6 patients with metastatic nonsquamous NSCLC who had not previously received chemotherapy were randomized to 1 of 3 arms: atezolizumab, carboplatin, and paclitaxel (Arm A; ACP), atezolizumab, bevacizumab (Avastin), carboplatin, paclitaxel (ABCP; Arm B), or bevacizumab, carboplatin, and paclitaxel (BCP; Arm C).
Results demonstrated a median OS of 19.2 months in Arm B versus 14.7 months in Arm C, reflecting a 22% reduction in the risk of death with the addition of atezolizumab to chemotherapy and bevacizumab (HR, 0.78; 95% CI, 0.64-0.96; P =.02). These data led to the December 2018 FDA approval of the quadruplet therapy for patients with metastatic nonsquamous NSCLC without EGFR or ALK aberrations, providing another standard treatment option to patients, said Chaft.
Although the regimen is not indicated for patients with EGFR or ALK aberrations, data from the trial showed that among a subset of 108 patients with these aberrations, the median progression-free survival (PFS) was 9.7 months in the ABCP arm versus 6.1 months in the BCP arm.7
In fact, recent data from an exploratory analysis from the trial were favorable enough that the quadruplet has emerged as a potential new standard of care for patients with EGFR-positive disease who progress on TKI treatment. Specifically, in patients with EGFR mutations, the median OS was not reached with ABCP versus 18.7 months with BCP (HR, 0.61; 95% CI, 0.29-1.28).8
Similarly designed, the phase III IMpower132 trial evaluated atezolizumab but with a backbone of carboplatin, cisplatin, and pemetrexed compared with carboplatin, cisplatin, and pemetrexed. At a median follow-up of 14.8 months, the median PFS was 7.6 months in the intent-to treat population with the quadruplet versus 5.2 months with chemotherapy alone arm (HR, 0.60; 95% CI, 0.49-0.72; P <.0001) with a favorable, though immature, median OS of 18.1 months with the quadruplet therapy versus 13.6 months with chemotherapy alone (HR, 0.81; 95% CI, 0.64-1.03; P =.0797).9
Data from the phase III IMpower130 trial demonstrated that atezolizumab, carboplatin, and nab-paclitaxel (Abraxane) could serve as yet another frontline regimen for patients with advanced nonsquamous NSCLC, said Chaft.10 At a median follow-up of 19 months, the median OS was 18.6 months and 13.9 months in the atezolizumab and chemotherapy-alone arms, respectively (HR, 0.79; 95% CI, 0.64-0.98; P =.033). In January 2019, the FDA granted a priority review to a supplemental biologics license application (sBLA) for the triplet regimen; the current action for the sBLA is December 2, 2019.
In light of the small subset of data from the IMpower150 trial, which suggested that patients with EGFR/ALK aberrations derived a benefit from the addition of atezolizumab to standard chemotherapy, investigators evaluated the PFS and OS of patients in the EGFR- and ALK-positive subgroup of the IMpower130 trial. Although PFS (HR, 0.75; 95% CI, 0.36-1.54) and OS (HR, 0.98; 95% CI, 0.41-2.31) favored the addition of atezolizumab, the data were not statistically significant.11
“Although of interest, given the initial IMpower150 data, we still do not know what to do with patients who have EGFR or ALK aberrations after progression on a TKI,” concluded Chaft.