Patients with advanced squamous non–small cell lung cancer (NSCLC) had a greater benefit from first-line treatment with the combination of atezolizumab (Tecentriq) plus chemotherapy vs chemotherapy alone in the randomized, phase III, IMpower131 clinical trial.¹ At the landmark of 12-month progression-free survival, the group receiving atezolizumab plus chemotherapy had a doubling in progression-free survival vs chemotherapy alone: 24.7% vs 12.0%, respectively.

The study enrolled all comers regardless of the level of programmed cell death ligand 1 (PD-L1) expression and supports the idea that checkpoint inhibitor immunotherapy is effective not only in patients who express high levels of PD-L1 but in those with very low PD-L1 levels.

“Until now, there have been few treatment options for squamous NSCLC. Our finding may provide a potential new treatment for this type of cancer,” said lead author Robert M. Jotte, MD, PhD, Medical Director and Co-Chair, US Oncology Thoracic Committee, Rocky Mountain Cancer Centers, Denver.

First Phase III Trial in Squamous NSCLC

Numerous studies are underway to determine optimal combinations of checkpoint inhibitor immunotherapy and other partners. IMpower131 is one of several studies to explore the use of a checkpoint inhibitor plus chemotherapy in NSCLC, and it is one of the first phase III trials to show a significant improvement in progression-free survival in advanced squamous NSCLC with an immunotherapy-based combination.

Until now, there have been few treatment options for squamous NSCLC. Our finding may provide a potential new treatment for this type of cancer.

— Robert M. Jotte, MD, PhD

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The number of studies showing the benefits of a checkpoint inhibitor plus chemotherapy is rapidly growing. At the 2018 American Association of Cancer Research (AACR) Annual Meeting, KEYNOTE-189 showed that pembrolizumab (Keytruda), another checkpoint inhibitor, plus chemotherapy improved overall survival by 51% compared with chemotherapy alone in nonsquamous NSCLC. (These findings from the AACR meeting were simultaneously published in The New England Journal of Medicine.²) At the 2018 ASCO Annual Meeting, results from KEYNOTE-407 were presented, showing that pembrolizumab plus carboplatin plus paclitaxel or nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) significantly improved both overall and progression-free survival compared with chemotherapy alone in metastatic squamous NSCLC irrespective of PD-L1 status.³

Squamous cell NSCLC accounts for about 30% of all cases of NSCLC, and it is considered difficult to treat. For many years, platinum-based doublet regimens have been used as first-line therapy for advanced squamous NSCLC, with a 5-year survival rate of less than 2%. The rationale for combining immunotherapy with chemotherapy rests on the hypothesis that cytotoxic chemotherapy kills normal and cancer cells indiscriminately and immunotherapy can “rev up” the immune system to attack the tumor cells.

“Tumor cells don’t repair themselves. The idea is that the immunotherapy will ‘bump up’ the immune system to attack those tumor cells,” Dr. Jotte explained at a press conference during the 2018 ASCO Annual Meeting, where he presented the study findings.

Dr. Jotte pointed out that recent studies have shown a benefit for immunotherapy plus chemotherapy in nonsquamous NSCLC. “Those findings, along with the results of this trial, may lead to a rapid change in clinical practice,” he added.

Study Details and Key Results

IMpower131 enrolled 1,021 patients with chemotherapy-naive stage IV squamous NSCLC with any level of PD-L1 expression. Patients were randomized 1:1:1 to one of three arms: arm A (atezolizumab plus carboplatin plus paclitaxel); arm B (atezolizumab plus carboplatin plus nab-paclitaxel); arm C (control arm, carboplatin plus nab-paclitaxel). Treatment in each arm was for 4 or 6 cycles. Arms A and B received atezolizumab -maintenance until disease progression or loss of clinical benefit. Arm C was followed with best supportive care. Arm A was not included in the analysis presented at the 2018 ASCO meeting. Dr. Jotte said, “There was no benchmark for comparing arm A.”

Regardless of the level of PD-L1 expression, 29% of all patients had a reduced risk of disease worsening or death with the immunotherapy combination arm (arm B) compared with chemotherapy (arm C). Twelve-month landmark progression-free survival was 24.7% with the immunotherapy combination vs 12.0% with chemotherapy. The median progression-free survival was 6.3 months in arm B vs 5.6 months in arm C (P = .0001). Progression-free survival was improved in the atezolizumab-plus-chemotherapy arm in all PD-L1–positive subgroups, with greater benefit observed in subgroups with higher PD-L1 expression. A trend toward improved progression-free survival was observed in patients with PD-L1–negative tumors.

The group with high PD-L1 expression had the best outcome with atezolizumab plus chemotherapy vs chemotherapy alone, but those who had low or negative PD-L1 expression also benefited from the immunotherapy combination compared with chemotherapy alone.

The confirmed objective response rate and the duration of response were better in all patients, as well as in the PD-L1–high and PD-L1–low subgroups, with atezolizumab plus chemotherapy vs chemotherapy alone. Among all patients, the confirmed objective response rate was 49% for the immunotherapy combination vs 41% for chemotherapy. Among patients with PD-L1–high tumors, the confirmed objective response rate was 60% vs 33%, respectively. Among patients with PD-L1–low tumors, the confirmed objective response rate was 52% vs 44%, respectively.

Among all patients in the trial, the median duration of response was 7.2 months with the immunotherapy combination vs 5.2 months with chemotherapy. In the PD-L1–high subgroup, the median duration of response was 18.7 months on the combination vs 5.3 months on chemotherapy. In the PD-L1–low subgroup, the median duration of response was 6.9 months vs 5.0 months, respectively.

At the first interim analysis, the median overall survival was 14.0 months for the atezolizumab-plus-chemotherapy arm vs 13.9 months for chemotherapy alone. Overall survival data are not mature and will be important to follow, said experts.

There were no new safety signals seen in this trial. The rate of grade 3 or 4 side effects was higher with the combined-modality treatment vs chemotherapy alone (68% vs 57%, respectively). Dr. Jotte said that the combination had a manageable toxicity profile, consistent with the known individual risks of atezolizumab and chemotherapy. The most common side effects thought to be related to atezolizumab were skin rash, hepatitis, colitis, and low thyroid hormone levels.

IMpower131 authors will continue to study which patients benefit the most from the immunotherapy combination and search for biomarkers to predict response. ■

DISCLOSURE: The study was funded by F. Hoffmann-La Roche Ltd. Dr. Jotte has received honoraria from, is on the speakers bureau for, and has received travel expenses from Bristol-Myers Squibb.

REFERENCES

1. Jotte RM, Cappuzzo F, Vynnychenko I, et al: IMpower 131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. 2018 ASCO Annual Meeting. Abstract LBA9000. Presented June 4, 2018.

2. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378:2078-2092, 2018.

3. Paz-Ares LG, Luft A, Tafreshi A, et al: Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel with or without pembrolizumab for patients with metastatic squamous non-small cell lung cancer. 2018 ASCO Annual Meeting. Abstract 105. Presented June 3, 2018.