Karen L. Reckamp, MD, MS
IMMUNOTHERAPY HAS revolutionized the treatment of lung cancer over the past several years. Although lung cancer is associated with immunosuppression at baseline for most patients, the addition of immune checkpoint inhibitors can overcome that suppression and lead to antitumor immune responses. Anti–programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) therapies have shown a survival benefit with manageable toxicities in patients with advanced non–small cell lung cancer (NSCLC), leading to approvals by the U.S. Food and Drug Administration and international agencies for immunotherapy with multiple drugs in advanced disease. Based on the significant improvements seen with immunotherapy in patients with metastatic NSCLC, immune checkpoint inhibitor therapy has been evaluated in patients with earlier-stage disease.
Logical Treatment Steps for Stage III NSCLC
STAGE III NSCLC is most commonly treated with multimodality therapy, including chemotherapy, radiation, and surgery. When surgical resection is not feasible for stage III disease, the standard treatment includes concurrent chemotherapy and radiation therapy. Despite improvements in survival using concurrent therapy over radiation therapy alone or sequential chemoradiation therapy, the median survival remained less than 2 years.1-3
Several approaches to improve outcomes for patients with unresectable stage III NSCLC have been attempted over the past decade. The addition of consolidation chemotherapy was shown to lead to increased toxicity without improving survival.4 The addition of targeted epidermal growth factor receptor (EGFR)-directed therapy did not lead to better outcomes for patients.5,6 Finally, a strategy to increase the radiation dose to 74 Gy also demonstrated more side effects without the benefit of increased survival.6
Due to enhanced survival from PD-1/PD-L1 antibody therapy seen in patients with metastatic NSCLC, the use of immune checkpoint inhibitors in earlier-stage, potentially curable disease was a logical next step. The interaction between radiation therapy and immunotherapy leads to possible synergy, resulting in an increase in antigen expression and presentation, followed by the release of inflammatory cytokines to enhance antitumor immune responses.
“The use of immune checkpoint inhibitors in earlier-stage, potentially curable disease was a logical next step.”— Karen L. Reckamp, MD, MS
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PACIFIC Trial: Initial and Updated Results
THE RANDOMIZED, phase III PACIFIC trial was the first to test this strategy in the clinic.7 In the study, 713 patients who received at least 2 cycles of platinum-based chemotherapy with radiation and did not develop disease progression were randomly assigned in a 2:1 manner to receive durvalumab at 10 mg/kg every 2 weeks up to 12 months or placebo. The primary endpoints were progression-free survival and overall survival in the intent-to-treat population. Baseline characteristics were similar in both arms. When PD-L1 expression was analyzed by at least 25% or less than 25%, numerically more patients in the durvalumab arm had at least 25% PD-L1 expression.
The initial results were presented after the interim analysis, with a median follow-up of 14.5 months.7 In the intent-to-treat population, progression-free survival was significantly prolonged at 16.8 months with durvalumab vs 5.6 months with placebo (hazard ratio [HR] = 0.52, P < .001).7 At 12 months, the progression-free survival rates were 55.9% vs 35.3% for durvalumab over placebo. The improvement was maintained at 18 months, with the rate of 44.2% in the durvalumab arm vs 27% in the placebo arm. This progression-free survival improvement was noted across most patient subgroups. Time to death or distant metastasis was also significantly longer with durvalumab, at 23.2 months vs 14.6 months for placebo (HR = 0.52, P < .0001).
In 2018, updated results, including initial overall survival data, were published in The New England Journal of Medicine8 (and discussed in detail in the December 25, 2018, issue of The ASCO Post). With a median follow-up of 25.2 months, the overall survival on intent-to-treat analysis was significantly increased among patients who received durvalumab compared with placebo, with a hazard ratio of 0.68 (P = .0025). The median overall survival was not reached in the durvalumab arm and was 28.7 months in the placebo arm. Progression-free survival continued to improve significantly with durvalumab (median = 17.2 months vs 5.6 months).
In a subgroup analysis, most groups achieved improved overall survival with durvalumab, including nonsmoking patients. The number of events in patients with EGFR mutation–positive NSCLC was too small to assess for overall survival. In an analysis using PD-L1 expression of 25% as a cutpoint, durvalumab was associated with improved survival regardless of PD-L1 expression. However, in an unplanned, post hoc analysis, patients with less than 1% PD-L1 expression did not achieve benefit from durvalumab.
It is important to note that the safety of durvalumab consolidation after concurrent chemotherapy and radiation therapy for unresectable stage III NSCLC was similar in both the durvalumab and placebo groups.7,8 Adverse events leading to treatment discontinuation were more common with durvalumab (15.4 % vs 9.8% with placebo). Immune-related adverse events also were more frequent in the durvalumab arm (24.2% vs 8.1%), as might be expected, but grade 3 or 4 immune-related adverse events were similar in both groups (3.4% for durvalumab and 2.6% for placebo).
Concerns regarding the possibility of pneumonitis led to scrutiny of this event in the PACIFIC trial. In the durvalumab arm, any-grade cough (35.4%) and pneumonitis or radiation pneumonitis (33.9%) were slightly more common in the durvalumab arm than with placebo (25.2% and 24.8%). Moreover, grade 3 or 4 pneumonitis or radiation pneumonitis was observed in 3.4% of patients who received durvalumab vs 2.6% of patients who received placebo.
“One concern is that patients with less than 1% PD-L1 expression may not derive the same benefit with consolidation durvalumab."— Karen L. Reckamp, MD, MS
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Unresolved Issues
BASED ON the superior efficacy in progression-free and overall survival as well as the manageable toxicity, durvalumab is a new standard of care as consolidation therapy for patients with unresectable stage III NSCLC without disease progression after concurrent chemoradiation therapy. Additional issues remain unresolved and pose questions regarding the use of immunotherapy in this population and potential selection of patients. One concern is that patients with less than 1% PD-L1 expression may not derive the same benefit with consolidation durvalumab. It is also possible that those with EGFR mutation–positive disease may not experience the same magnitude of benefit, as seen in the total population in the PACIFIC trial. Ongoing trials are also addressing earlier-stage NSCLC and the use of immunotherapy in the perioperative setting, with the goal of improving survival and quality of life for more patients with lung cancer. ■
DISCLOSURE: Dr. Reckamp is a consultant/advisor to Amgen, Ariad, Astellas Pharma, Euclises, Tesaro, Boehringer Ingelheim, and Takeda; and has received institution research funding from Bristol-Myers Squibb, Pfizer, Ariad, Xcovery, Adaptimmune, Genentech/Roche, Boehringer Ingelheim, AbbVie, Acea Biosciences, and Loxo.
REFERENCES
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2. Belani CP, Wang W, Johnson DH, et al: Phase III study of the Eastern Cooperative Oncology Group (ECOG 2597): Induction chemotherapy followed by either standard thoracic radiotherapy or hyperfractionated accelerated radiotherapy for patients with unresectable stage IIIA and B non-small-cell lung cancer. J Clin Oncol 23:3760-3767, 2005.
3. Senan S, Brade A, Wang LH, et al: PROCLAIM: Randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 34:953-962, 2016.
4. Hanna N, Neubauer M, Yiannoutsos C, et al: Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: The Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 26:5755-5760, 2008.
5. Kelly K, Chansky K, Gaspar LE, 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: SWOG S0023. J Clin Oncol 26:2450-2456, 2008.
6. Bradley JD, Paulus R, Komaki R, et al: Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): A randomised, two-by-two factorial phase 3 study. Lancet Oncol 16:187-199, 2015.
7. Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377:1919-1929, 2017.
8. Antonia SJ, Villegas A, Daniel D, et al: Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 379:2342-2350, 2018.
