Atezolizumab Survival Advantage Continues To Be Seen in Frontline PD-L1–High NSCLC

Continued follow-up of the phase 3 IMpower110 trial (NCT02409342) indicated that clinically meaningful survival and response benefit was maintained with frontline atezolizumab (Tecentriq) versus chemotherapy in patients with PD-L1–high, wild-type (WT) nonsquamous or squamous non–small cell lung cancer (NSCLC). Findings from the updated analysis that included a review of overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and duration of response (DOR) end points were presented during the 2020 World Conference on Lung Cancer Singapore.¹

With a median follow up of 31.3 months, the median OS was 20.2 months with atezolizumab (n = 107) versus 14.7 months with chemotherapy (n = 98) in the high PD-L1 expression WT group. The 6-month OS rate was 76.5% versus 70.4%, respectively. The 12-month OS rate was 66.1% versus 52.3%, respectively (HR, 0.76; 95% CI, 0.54-1.09).

The median PFS was 8.2 months with atezolizumab compared with 5.0 months with chemotherapy in the high PD-L1 expression WT population. The 6-month PFS rate was 60.3% versus 38.3%, respectively. The 12-month PFS rate was 39.2% versus 19.2%, respectively (HR, 0.59; 95% CI, 0.43-0.81; P = .0010). Moreover, the confirmed ORR was 40.2% with atezolizumab versus 28.6% with chemotherapy, and the median DOR was 38.9 months versus 8.3 months, respectively.

“Updated data from the IMpower110 [study] continue to support the use of atezolizumab for the first-line treatment of patients with non–small cell lung cancer whose tumors have high PD-L1 expression,” said Roy S. Herbst, MD, PhD, Ensign Professor of Medicine and professor of pharmacology, and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital, as well as the associate cancer center director for Translational Research at Yale Cancer Center, in a virtual presentation of the data.

On May 18, 2020, the FDA approved atezolizumab as frontline treatment for patients with metastatic NSCLC whose tumors have high PD-L1 expression, as determined by an FDA-approved test, and do not harbor EGFR or ALK aberrations based on the interim results of the IMpower110 trial.²

Findings from the primary analysis, which were reported with a median follow up of 15.7 months, demonstrated that the median OS was 20.2 months with atezolizumab versus 13.1 months with chemotherapy in the high PD-L1 expression WT group. The 6-month OS rate was 76.3% months versus 70.1%, respectively. The 12-months OS rate was 64.9% versus 50.6%, respectively (HR, 0.59; 95% CI, 0.40-0.89; P = .0106).

The primary end point of the IMpower110 trial was OS in the WT population, with key secondary end points including investigator-assessed PFS, ORR, and DOR per RECIST v1.1 criteria. Notably, OS was tested in a hierarchical design, first in the high PD-L1 expression WT population (n = 205), followed by the high or intermediate PD-L1 expression WT population (n = 328), followed by the any PD-L1 expression WT population (n = 554).

Patients were randomized 1:1 to receive 1200 mg of atezolizumab every 3 weeks followed by atezolizumab maintenance therapy until progressive disease or loss of clinical benefit, or chemotherapy followed by maintenance therapy until progressive disease. In the chemotherapy arm, patients with nonsquamous NSCLC received cisplatin/carboplatin plus pemetrexed (Alimta) followed by pemetrexed maintenance therapy, and patients with squamous NSCLC received cisplatin/carboplatin plus gemcitabine followed by best supportive care.

No crossover was permitted for maintenance therapy.

Eligible patients had to have chemotherapy-naïve, stage IV nonsquamous or squamous NSCLC. Patients were PD-L1–selected with the VENTANA SP142 Immunohistochemistry (IHC) assay and stratified by sex, ECOG performance status, PD-L1 IHC expression, and histology.

Despite the numerical improvements in PFS and OS with atezolizumab in the high PD-L1 expression WT group, the updated data failed to show a statistically significant OS improvement with atezolizumab versus chemotherapy in patients with high or intermediate PD-L1 WT NSCLC. As such, OS in the any PD-L1 expression WT population was not formally tested.

Patients with high or intermediate PD-L1 expression derived a median OS of 19.9 months with atezolizumab versus 16.1 months with chemotherapy (HR, 0.87; 95% CI, 0.66-1.14; P = .3091). The median PFS was 7.3 months versus 5.5 months, respectively (HR, 0.64; 95% CI, 0.50-0.82; P = .0004).

The confirmed updated ORR with atezolizumab was 33.7% versus 32.1% with chemotherapy in patients with high or intermediate PD-L1 expression. The median DOR was 38.9 months with atezolizumab versus 5.8 months with chemotherapy.

“With 17 months of additional follow up, atezolizumab continued to show a numerical overall survival benefit in the PD-L1–high or –intermediate population; however, this was not statistically significant,” explained Herbst. “Therefore, overall survival was not formally tested in any PD-L1 population, and the presented analysis in this population is descriptive only.”

Findings from the primary analysis demonstrated that the median OS was 18.9 months with atezolizumab versus 14.7 months with chemotherapy in the any PD-L1 expression population (HR, 0.85; 95% CI, 0.69-1.04; P = .1070). The updated median PFS was 5.8 months versus 5.6 months, respectively (HR, 0.72; 95% CI, 0.60-0.86; P = .0004).

In the any PD-L1 expression group, the confirmed ORR was 31.4% with atezolizumab versus 32.1% with chemotherapy. The median DOR was 26.3 months with atezolizumab versus 5.7 with chemotherapy.

Notably, a similar proportion of patients across the 3 subpopulations received subsequent non-protocol cancer therapy; however, more patients with high PD-L1 expression received subsequent therapy and subsequent immunotherapy in the chemotherapy arm versus the atezolizumab arm at the interim and updated OS analyses.

At the interim analysis, 24.3% (n = 26) of patients in the atezolizumab arm received 1 or more therapies, including immunotherapy, chemotherapy, targeted therapy, and unknown therapy compared with 46.9% (n = 46) of patients in the chemotherapy arm. At the updated OS analysis, 35.5% (n = 38) and 54.1% (n = 53) of patients with high PD-L1 expression in the atezolizumab and chemotherapy arms, respectively, received subsequent cancer therapies.

After adjusting for subsequent immunotherapy use, the median OS was 20.2 months with atezolizumab versus 13.0 months with chemotherapy in high PD-L1 expression WT patients (HR, 0.69; 95% CI, 0.48-0.99).

Regarding safety, the median treatment duration was 5.3 months with atezolizumab, 3.5 months with pemetrexed, 2.6 months with gemcitabine, 2.3 months with carboplatin, and 2.1 months with cisplatin.

No new or unexpected toxicities were observed with atezolizumab. All-grade, any-cause adverse effects (AEs) were observed in 92% of patients with atezolizumab compared with 95.1% of patients with chemotherapy. Of these, 62.9% and 85.2% were treatment related, respectively.

All-cause AEs with a greater than 5% difference between study arms that were more frequent with chemotherapy included anemia, nausea, neutropenia, constipation, thrombocytopenia, vomiting, blood creatinine, decreased platelet count, leucopenia, decreased neutrophil count, and alopecia. AEs that were more frequent with atezolizumab included pyrexia, increased aspartate aminotransferase, rash, nasopharyngitis, arthralgia, pruritus, and hypothyroidism.

Grade 3 or 4 AEs were observed in 33.9% of patients in the atezolizumab arm versus 53.2% in the chemotherapy arm. Grade 3 or 4 treatment-related AEs (TRAEs) were observed in 14.3% and 44.9% of patients, respectively. Serious AEs occurred in 31.8% and 29.3% of patients, respectively. Of these, 9.4% and 15.6% were treatment related.

Additionally, 4.2% of patients in each arm experienced grade 5 AEs, with 1 grade 5 TRAE observed in the chemotherapy arm.

AEs that led to treatment withdrawal occurred in 7.3% of patients who received atezolizumab compared with 17.1% of patients who received chemotherapy.

Finally, immune-mediated AEs were observed in 46.2% of patients with atezolizumab versus 18.3% of patients with chemotherapy. Of these, 8.7% and 1.5% were grade 3 or 4, respectively. Additionally, 13.3% and 1.5% of immune-mediate AEs required corticosteroids, respectively.

References:

1. Herbst RS, de Marinis F, Giaccone G, et al. IMpower110: updated OS analysis of atezolizumab vs platinum-based hemotherapy as first-line treatment in PD-L1–selected NSCLC. Presented at: 2020 World Conference on Lung Cancer Singapore. January 28-31, 2021. Abstract FP13.03.

2. FDA approves Genentech’s Tecentriq as a first-line monotherapy for certain people with metastatic non-small cell lung cancer. Published May 18, 2020. Accessed January 28, 2021. https://bit.ly/3fYAw29.