Karen Kelly, MD
Immune checkpoint inhibitors have had a dramatic impact on survival for patients with stage IV non–small cell lung cancer (NSCLC), with whispers that a cure might be achieved in a subset of patients. In typical fashion, active new agents are evaluated in earlier stages of disease.
Stage III NSCLC afflicts approximately one-third of patients diagnosed with lung cancer each year. Although it is a curative disease with combined-modality treatment, the cure rate is low, ranging from 36% (stage IIIA) to 13% (stage IIIC).1 It was 2003 when Radiation Therapy Oncology Group (RTOG) 9410 showed concurrent chemoradiotherapy was superior to sequential therapy in stage III NSCLC.2 Many years of unsuccessful phase III trials evaluating induction, consolidation, or maintenance systemic therapy, integration of the novel agents pemetrexed (Alimta) and cetuximab (Erbitux) into the chemoradiation backbone, and higher doses of radiation passed before the immune checkpoint inhibitor durvalumab (Imfinzi) achieved the elusive goal of positivity.
Context of PACIFIC Trial Findings
The international PACIFIC trial randomized 713 patients with stage III disease in a 2:1 ratio to receive durvalumab or placebo consolidation for 1 year after a concurrent chemoradiation regimen.3 [See the December 25, 2017, issue of The ASCO Post for more details on the PACIFIC trial.] The trial met its first co-primary progression-free survival endpoint, producing an impressive hazard ratio of 0.52 with a P value < .001 vs placebo, with an early separation of the survival curve at 3 months and a plateau effect. At second glance, it is noted that the placebo group performed below expectation, which has been a criticism of this study. However, one must take into account this trial randomized patients after definitive treatment, and survival data in this setting are very limited.
There are two studies that enrolled patients after completion of chemoradiation—the U.S. Southwest Oncology Group (SWOG) S0023 trial evaluating maintenance gefitinib (Iressa) vs placebo and the international START trial of tecemotide vs placebo.4,5 The median progression-free survival times were 11.7 and 8.4 months, respectively, as compared with 5.6 months in the placebo group in the PACIFIC trial. Although the additional analysis is needed to understand the poorer outcome in the placebo group, the median progression-free survival of 16.8 months with durvalumab is unprecedented. Data on the second co-primary endpoint of overall survival are immature.
We anxiously await the answer to this more significant question, with great hope that the magnitude of the progression-free survival benefit seen will be sufficient to clear the overall survival hurdle and increase the cure rate for patients with stage III NSCLC. Nonetheless, the progression-free survival improvement with durvalu-mab represents a clinically meaningful outcome that is worthy of being incorporated into practice, pending regulatory approval.
Question of Routine Molecular Testing
All subgroups benefited from durvalumab except the small group of patients with an epidermal growth factor receptor (EGFR)-mutated tumor. This is not surprising, given that immune therapies have consistently shown no benefit in such patients with stage IV disease. These patients should not receive durvalumab, and the finding raises the question of routine molecular testing in patients with stage III disease, especially those with adenocarcinoma histology.
Durvalumab consolidation after chemoradiation is the first major advance in the treatment of stage III NSCLC in decades.— Karen Kelly, MD
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Tumor programmed cell death ligand 1 (PD-L1) expression was not predictive of outcome, but there was a trend toward longer progression-free survival with higher PD-L1 expression. These data need to be viewed cautiously because 37% of patients had an unknown PD‑L1 status. Regardless, an in-depth analysis of outcome by multiple PD-L1 expression levels will be important to optimize therapy.
A commonly asked question concerns the outcome in patients with no PD-L1 expression and ≥ 50% PD-L1 expression. Beyond PD-L1 expression, tumor mutational burden and inflamed gene signatures are proving to be complementary biomarkers, which may further refine immune-responsive and -refractory patients.6-8 An evaluation of these markers (and others) would provide an unprecedented snapshot into understanding the tumor-host treatment dynamics in a curative setting, which may quickly influence future clinical trial designs.
Concern about immunotherapy inducing higher rates of pneumonitis in patients receiving definitive radiation was substantiated, but the increased rate was predominantly due to grade 1 and 2 events. Symptomatic grade 3 or 4 pneumonitis rates were low and similar between the arms (3.4% and 2.6%), and grade 5 pneumonitis occurred in 4 patients (0.8%) receiving durvalumab and 3 patients (1.3%) receiving placebo. Overall, these data should provide reassurance to patients and treating physicians that immunotherapy can be safely administered after chemotherapy and radiation.
In summary, durvalumab consolidation after chemoradiation is the first major advance in the treatment of stage III NSCLC in decades. Patients and investigators are to be commended on the swift study execution and data release. Patience will be required while we await the overall survival outcome. Meanwhile, new trials building upon these results are in development. Incorporating immunotherapy into the concurrent chemoradiation backbone and consolidation immunotherapy combinations are two major platforms being pursued. Adjuvant and neoadjuvant immunotherapy trials in resectable NSCLC are ongoing as well. The immunotherapy revolution across all stages of lung cancer is fast and furious. Undoubtedly, we are on the cusp of curing more lung cancer patients with immunotherapy. ■
Dr. Kelly is Professor of Medicine and Associate Director for Clinical Research, University of California Davis Comprehensive Cancer Center.
DISCLOSURE: Dr. Kelly reported no conflicts of interest relating to this study; however, she is on the data and safety monitoring board for other AstraZeneca trials.
1. Goldstraw P, et al: The IASLC Lung Cancer Staging Project. J Thorac Oncol 11:39-51, 2016.
2. Curran WJ, et al: Long-term benefit is observed in a phase III comparison of concurrent versus sequential chemo-radiation for patients with unresected stage III NSCLC. 2003 ASCO Annual Meeting. Abstract 2499.
3. Antonia SJ, et al: Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med 377:1919-1929, 2017.
4. Kelly K, et al: Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non–small-cell lung cancer. J Clin Oncol 26:2450-2456, 2008.
5. Butts C, et al: Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START). Lancet Oncol 15:59-68, 2014.
6. Carbone DP, et al: First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 376:2415-2426, 2017.
7. Prat A, et al: Immune-related gene expression profiling after PD-1 blockade in non-small cell lung carcinoma, head and neck squamous cell carcinoma, and melanoma. Cancer Res 77:3540-3550, 2017.
8. Ayers M, et al: IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 127:2930-2940, 2017.