Dissecting the Data With Immune-Based Combinations in Advanced Nonsquamous NSCLC

Jonathan Dowell, MD

The paradigm of advanced nonsquamous non–small cell lung cancer (NSCLC) is now one that necessitates discussions regarding the use of combination chemoimmunotherapy, combination immunotherapy, and single-agent immunotherapy, explained Jonathan Dowell, MD.

In a presentation during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Dowell, MD, professor of Internal Medicine at the University of Texas Southwestern Medical Center and chief of Hematology/Oncology at Dallas VA Medical Center, discussed the data that support the use of chemoimmunotherapy in the frontline setting.

KEYNOTE-189

KEYNOTE-189 was a phase 3 trial that evaluated frontline pembrolizumab (Keytruda) plus chemotherapy versus placebo plus chemotherapy in patients with stage IV nonsquamous NSCLC without EGFR and ALK mutations. Eligible patients were randomized to 200 mg of pembrolizumab plus platinum/pemetrexed every 3 weeks (n = 410) versus the same schedule of placebo plus platinum/pemetrexed (n = 206) for 4 cycles followed by maintenance therapy with pemetrexed plus pembrolizumab or placebo, depending on randomization.¹

Patients with any level of PD-L1 expression were eligible for enrollment, and baseline assessment showed that approximately 30% of patients in each arm had a PD-L1 tumor proportion score (TPS) of less than 1%, 1% to 49%, and 50% or greater.

Progression-free survival (PFS) and overall survival (OS), which served as co-primary end points of the trial, favored the pembrolizumab arm in the overall population (HR, 0.52; HR, 0.49, respectively). Moreover, PFS favored the addition of pembrolizumab to standard platinum-based chemotherapy across TPS thresholds (TPS <1%, HR, 0.75; TPS 1% to 49%, HR, 0.55; TPS ≥50%, HR, 0.36), though the benefit in the TPS less than 1% group did not reach statistical significance, explained Dowell.

In the OS analysis, all 3 groups demonstrated statistical significance in favor of pembrolizumab. As in the PFS analysis, the greatest benefit was reported in the TPS 50% or greater group (HR, 0.42), followed by the TPS 1% to 49% group (HR, 0.55%), and the TPS less than 1% group (HR, 0.59).

Updated data demonstrated sustained, statistically significant OS benefit, irrespective of PD-L1 expression. In the overall population, the median OS with pembrolizumab was more than double that with chemotherapy alone, at 22 months versus 10.7 months, respectively (HR, 0.56). Additionally, the 2-year OS rate was 45.5% with pembrolizumab versus 29.9% with chemotherapy alone.²

Adverse effects (AEs) were manageable, said Dowell, although a slightly higher percentage of patients discontinued treatment in the pembrolizumab arm versus the chemotherapy-alone arm due to AEs, at 33.6% versus 16.3%, respectively. Grade 3 or greater immune-related AEs (irAEs) occurred in 10.9% and 4.5% of patients, respectively.

In August 2018, the triplet received full approval for the frontline treatment of patients with driver-negative advanced nonsquamous NSCLC.

IMpower150

IMpower150 was a 3-arm phase 3 trial that evaluated atezolizumab (Tecentriq) plus chemotherapy, atezolizumab and bevacizumab (Avastin) plus chemotherapy, and bevacizumab plus chemotherapy in patients with stage IV recurrent or metastatic NSCLC. Eligible patients were randomized to 1200 mg of intravenous atezolizumab plus carboplatin/paclitaxel every 3 weeks (ACP; n = 402), the same schedule of atezolizumab and carboplatin/paclitaxel plus bevacizumab (ABCP; n = 400), or bevacizumab plus carboplatin/paclitaxel (BCP; n = 400), followed by maintenance therapy with atezolizumab, atezolizumab/bevacizumab, or bevacizumab, respectively.³

In contrast to the KEYNOTE-189 trial, PD-L1 expression was evaluated with the Ventana SP142 assay and demonstrated that approximately 20% of patients had tumor cell (TC) or immune cell high expression (TC3; IC3), approximately 30% had intermediate expression (TC2/3; IC2/3), and approximately 50% had low expression (TC1/2/3; IC1/2/3).

Interim OS data demonstrated that the addition of atezolizumab to chemotherapy led to a 5-month improvement in median OS versus bevacizumab/chemotherapy in the wild-type population (HR, 0.78). However, this was not statistically significant.

The results did demonstrate superior PFS (HR, 0.59) and OS (HR, 0.78) with ABCP versus BCP in the wild-type population. Moreover, all landmark analyses favored ABCP; the 18-month PFS rates were 27% in the ABCP arm versus 8% in the BCP arm, and the 24-month OS rates were 43% and 34%, respectively.

In the subgroup analysis, all patients derived a PFS benefit from ABCP versus BCP, regardless of PD-L1 expression. Though, higher PD-L1 expression was associated with a greater benefit from atezolizumab.

The subgroup of patients with pretreated EGFR- and ALK-mutant NSCLC, though small, also experienced prolonged OS with the addition of atezolizumab, in both the 4-drug (HR, 0.50) and 3-drug arms (HR, 0.82).

“The hazard ratio, though trending in the right direction, does cross unity, so [we don’t have] conclusive [evidence] of a survival advantage for the 4-drug arm compared with chemotherapy alone,” said Dowell. “However, we did see an OS benefit in patients with liver metastases that does reach statistical significance, with a hazard ratio of 0.54.”

In terms of safety, approximately 30% of patients discontinued treatment due to AEs in the ABCP arm versus 25% in the BCP arm and 13% in the ACP arm.

“When we looked specifically at irAEs, it wasn’t clear that there were more irAEs with ABCP compared with ACP,” said Dowell.

In December 2018, the 4-drug regimen received regulatory approval for the first-line treatment of patients with metastatic nonsquamous NSCLC, exclusive of patients with EGFR and ALK aberrations.

IMpower132

Atezolizumab was also evaluated in the phase 3 IMpower132, in which patients with stage IV nonsquamous NSCLC without EGFR or ALK mutations were randomized to 1200 mg of atezolizumab plus a target area under the curve (AUC) of 6 mg/mL of carboplatin, or 75 mg/m2 of cisplatin plus 500 mg/m2 of pemetrexed every 3 weeks for 4 or 6 cycles (n = 292) versus the same schedule of carboplatin or cisplatin/pemetrexed alone (n = 286) followed by 4 or 6 cycles of maintenance therapy with atezolizumab/pemetrexed or pemetrexed, respectively.⁴

Baseline characteristics demonstrated that patients were well matched between arms. Approximately half of patients in each arm were PD-L1 positive, although the majority were PD-L1 low.

The results demonstrated a statistically significant improvement in PFS with the addition of atezolizumab, at 7.6 months versus 5.2 months with chemotherapy alone (HR, 0.60; 95% CI, 0.49-0.72; P < .0001). The 12-month PFS rates were 33.7% and 17%, respectively, and the benefit was observed across all key subgroups.

The median OS was 18.1 months in the atezolizumab arm versus 13.6 months in the chemotherapy-alone arm (HR, 0.81; 95% CI, 0.64-1.03; P < .0797).

“There was a trend toward improved OS that favored the addition of atezolizumab. Although the hazard ratio was 0.81, it does cross unity and was not statistically significant,” said Dowell.

As opposed to KEYNOTE-189 and IMpower150, where higher PD-L1 expression correlated with improved outcomes, patients with PD-L1–high (HR, 0.46) and PD-L1–negative disease (HR, 0.45) experienced the greatest PFS benefit with APP compared with patients with PD-L1–low disease (HR, 0.80).

In terms of safety, treatment-related AEs were manageable and were consistent with the known safety profiles of chemotherapy and immunotherapy alone, said Dowell. Approximately 50% patients in the APP arm experienced a grade 3/4 TRAE. However, only 15% of patients discontinued atezolizumab due to AEs.

“OS, though numerically improved, did not meet its primary analysis, and we have not seen a subsequent analysis showing clear OS benefit with the addition of atezolizumab,” said Dowell.

IMpower130

In the phase 3 IMpower130 trial, patients with stage IV nonsquamous NSCLC were randomized 2:1 to 1200 mg of atezolizumab and a target AUC of 6 mg/mL of carboplatin every 3 weeks plus 100 mg/m2 of nab-paclitaxel (Abraxane) weekly for 4 to 6 cycles, followed by atezolizumab maintenance (n = 483) versus the same schedule of carboplatin and nab-paclitaxel, followed by observation or 500 mg/m2 of pemetrexed maintenance every 3 weeks (n = 240). As in IMpower150, patients with EGFR- or ALK-mutant disease were eligible for enrollment if they had progressed on targeted therapy.⁵

“There were no major imbalances in patient characteristics, and about 20% of patients were PD-L1 high, about 30% were PD-L1 low, and about 50% were PD-L1 negative,” said Dowell.

The primary analysis showed a significant improvement in PFS, favoring atezolizumab (HR, 0.64; 95% CI, 0.54-0.77; P < .001). The difference in median PFS was modest; however, the 12-month PFS rates were 29.1% with atezolizumab versus 14.1% with chemotherapy alone.

Similarly, there was a statistically significant improvement in OS that favored the addition of atezolizumab (HR, 0.79; 95% CI, 0.64-0.98; P = .033). The difference in median OS was more pronounced, at 18.6 months with atezolizumab versus 13.9 months with chemotherapy alone. The 2-year OS rates were 39.6% and 30%, respectively.

“There were trends in the right direction for each subgroup, but the majority crossed unity [in the forest plot, including the PD-L1 subgroups,” said Dowell.

Regarding safety, 45% of patients experienced an irAE; however, the majority of them were grade 1/2.

In December 2019, the FDA approved the triplet for the first-line treatment of patients with advanced nonsquamous NSCLC who do not harbor EGFR or ALK aberrations. 

“It’s always hazardous to do cross-trial comparisons, but in this case, it’s worth looking at the differences,” said Dowell, who provided a look at the topline OS results from each study (Table).

“There are certainly differences in toxicity and cost that might influence treatment decisions. The liver metastases data [with the 4-drug regimen in IMpower150] is interesting, but we’d like to see it confirmed. The EGFR and ALK data [from IMpower150] are interesting, and larger studies are ongoing to confirm whether patients who progress after targeted therapy should get chemotherapy alone or chemoimmunotherapy,” concluded Dowell.

Of note, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) with or without chemotherapy, and pembrolizumab and atezolizumab monotherapy in PD-L1–high NSCLC are FDA-approved options for the first-line treatment of patients with advanced NSCLC.

References

1. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small–cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005
2. Gadgeel S, Rodrigues-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non–small–cell lung cancer. J Clin Oncol. 2020;38(suppl 14):1505-1517. doi:10.1200/JCO.19.03136
3. Socinski MA, Jotte R, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. 2018;36(suppl 15):9002. doi:10.1200/JCO.2018.36.15_suppl.9002
4. Papadimitrakopoulou V, Cobo M, Bordoni R, et al. IMpower132: PFS and safety results with 1L atezolizumab + carboplatin/cisplatin + pemetrexed in stage IV non-squamous NSCLC. J Thorac Oncol. 2018;13(10):S332-S333. doi:10.1016/j.jtho.2018.08.262
5. Cappuzzo F, McCleod M, Hussein M, et al. IMpower130: progression-free survival (PFS) and safety analysis from a randomised phase III study of carboplatin + nab-paclitaxel (CnP) with or without atezolizumab (atezo) as first-line (1L) therapy in advanced non-squamous NSCLC. Ann Oncol. 2018;29(supp 8):LBA53. doi:10.1093/annonc/mdy424.065