Updates of Key Trials in Metastatic Non–Small Cell Lung Cancer: KEYNOTE-024 and AvaALL


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“Immunotherapy can modify the tumor microenvironment, and vice versa—chemotherapy can boost immune response.”
— Matthew Gubens, MD, MS

IMMUNOTHERAPY AND ANTIANGIOGENESIS were highlighted in a session on metastatic non–small cell lung cancer (NSCLC) at the Best of ASCO New Orleans meeting. Matthew Gubens, MD, MS, presented the selected abstracts from the ASCO Annual Meeting.1 Dr. Gubens is Associate Professor of Thoracic Medical Oncology at the University of California, San Francisco. 

Updated Survival Data From KEYNOTE-024 

“ONGOING STUDIES in lung cancer are looking at how immunotherapy combinations might change the tumor microenvironment,” Dr. Gubens said, before discussing progression after the next line of therapy—also known as second progression, or PFS2—and updated overall survival data among patients enrolled in the KEYNOTE-024 trial.2 

In KEYNOTE-024,3 305 untreated patients with advanced NSCLC, a programmed cell death ligand 1 (PD-L1) tumor proportion score ≥ 50%, and no sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations were randomized 1:1 to pembrolizumab (Keytruda) at 200 mg every 3 weeks for up to 2 years (n = 154) or platinum-doublet chemotherapy (n = 151).

“It required the screening of 1,900 patients to get 1,600 patients evaluable for PD-L1, of whom 30% had the biomarker,” noted Dr. Gubens. “So it is important to note that it is only a minority of patients who have this high PD-L1 expression.” 

After a median follow-up of 11.2 months, progression-free survival with pembrolizumab was highly statistically significant and superior to chemotherapy (HR = 0.50, P < .001). “But it wasn’t just on the basis of progression-free survival that the study was closed early,” he said. “It was the fact that the secondary endpoint of overall survival was also statistically significantly better, with a hazard ratio of 0.6 and a P value of .005, even though the data were not yet mature at 11.2 months.” 

According to Dr. Gubens, PFS2 is not often measured in lung cancer. The European Medicines Association first defined it in 2012 as the time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurs first. In KEYNOTE-024, however, it was used to assess the impact of crossover on overall survival assessment and whether or not therapy positively impacted efficacy in the next line of therapy. In other words, could pembrolizumab lead to better responses to chemotherapy? 

Of the patients in the study randomized to chemotherapy, 79 crossed over to pembrolizumab, and an additional 12 received anti– programmed cell death protein 1 (PD-1) therapy outside of crossover, for a 60.3% crossover rate in the intent-to-treat population. 

Second-line therapy was received by 48 patients (31.2%) in the pembrolizumab arm and 97 (64.2%) in the chemotherapy arm. The majority of patients in the pembrolizumab arm who got to the second line (88%) received an appropriate platinum doublet, and the median duration of time on that doublet was 3.6 months. Of the 79 patients who crossed over to pembrolizumab from the chemotherapy arm, the median treatment duration was 4.2 months. Twelve patients received nivolumab or pembrolizumab off study, with a median treatment duration of about 3 months, and 6 received another chemotherapy, with a median duration of 1.9 months. 

NSCLC TREATMENT UPDATE

  • Updated overall survival data from the KEYNOTE-024 trial showed a continued overall survival benefit with first-line pembrolizumab vs chemotherapy in advanced NSCLC patients with PD-L1 tumor expression ≥ 50%.
  • The phase III MYSTIC study compared first-line durvalumab alone or combined with tremelimumab, to platinum-based standard-of-care chemotherapy in previously untreated patients with metastatic non–small cell lung cancer and tumors with ≥ 25% PD-L1 expression. Progression-free survival was not improved.
  • In patients with advanced nonsquamous NSCLC with disease progression on therapy (including bevacizumab), bevacizumab added to standard of care is not superior to standard of care alone.

With regard to PFS2, there was a statistically significant benefit for starting treatment with pembrolizumab vs chemotherapy. The median PFS2 was 18.3 months with pembrolizumab vs 8.4 months with chemotherapy (HR = 0.54, P < .001), noted Dr. Gubens. 

“After 19 months of median follow-up, we see overall survival remains quite robust,” he added. “We still have not seen median overall survival, but it appears it will be well over 20 months, compared to 14.5 months in the chemotherapy arm.” Despite an effective crossover rate of about 60%, there remained a high degree of separation of overall survival curves. According to the investigators, these data support pembrolizumab as a standard of care for first-line treatment of NSCLC with PD-L1 expression ≥ 50%. 

But according to Dr. Gubens, this study is “practice-affirming,” rather than practice-changing. Patients with nonsquamous disease should be tested for PD-L1, and if expression is ≥ 50%, pembrolizumab should be considered superior to chemotherapy due to its clear survival benefit. However, patients with EGFR, ALK, and ROS1 mutations should not start with pembrolizumab, he cautioned. As to the PFS2 analysis, he argued that more data are needed to make any definitive judgment. 

Future of Immunotherapy in NSCLC 

REGARDING FUTURE DIRECTIONS, “sequence can matter,” he said. “Immunotherapy can modify the tumor microenvironment, and vice versa—chemotherapy can boost immune response. This is something we should bear in mind as we design our studies.” 

Phase III data on first-line chemotherapy/immunotherapy approaches are emerging, and a carboplatin/pemetrexed/pembrolizumab combination is now approved by the U.S. Food and Drug Administration in nonsquamous NSCLC. Dr. Gubens expressed caution regarding this approval, due to the small KEYNOTE-021 cohort of 123 patients, who demonstrated improvements in response rate and progression-free survival but not in overall survival, and suggested awaiting results from fully accrued phase III trials, which are pending. Another angle for first-line therapy could be in combining immunotherapy agents, he said. 

To that end, the phase III MYSTIC study compared first-line durvalumab (Imfinzi) alone, or in combination with tremelimumab, to platinum-based standard-of-care chemotherapy in previously untreated patients with metastatic non–small cell lung cancer whose tumors express PD-L1 on 25% or more of their cancer cells. Progression-free survival, the primary endpoint, was not improved.4 

“We’ve learned that the the MYSTIC study, unfortunately, was negative, suggesting chemotherapy was superior to durvalumab and durvalumab plus tremelimumab, though we don’t have the data in hand yet,” he said. “But stay tuned. There’s a lot happening in this forum.” 

AvaALL Trial of Bevacizumab 

“ANTIANGIOGENESIS IN NSCLC has had a long and storied history, but the benefits have been somewhat modest,” said Dr. Gubens. “As part of the development strategy, there have been studies in different tumor types looking at the utility of bevacizumab [Avastin] beyond progression, and whether, beyond the first line of therapy, it can play a role in helping to facilitate subsequent lines of therapy.” 

AvaALL was the first randomized phase III study to analyze the efficacy of bevacizumab beyond progression in advanced NSCLC.5 A total of 485 patients with advanced nonsquamous NSCLC who had received between 4 and 6 cycles of chemotherapy plus bevacizumab, and at least 2 cycles of maintenance bevacizumab, were randomized after first progression to second-line standard of care with investigator’s choice of docetaxel, pemetrexed (Alimta), or erlotinib (Tarceva), with or without bevacizumab. The primary endpoint was overall survival. 

Median overall survival for bevacizumab plus standard of care was 11.9 months, vs 10.2 months for standard of care alone (hazard ratio [HR] = 0.84, P = .1044). “There’s not much daylight between the two overall survival curves,” said Dr. Gubens. Improvement in progression-free survival in the third-line setting, however, was significant: 3.5 months for bevacizumab vs 2.4 months for standard of care (P = .0047). Toxicity, as expected, was higher with the addition of bevacizumab, but no new safety signals were identified. Although the primary endpoint was not met, the data suggest a positive trend for continued bevacizumab plus standard of care after first progression, as opposed to standard of care alone, the investigators reported. 

“But this is not practice-changing,” Dr. Gubens maintained. “This is a negative phase III study. The modest improvement was numerical, and the only statistically significant benefits were in secondary endpoints and modest in magnitude.” As with similar trials, he added, the struggle is in determining which patients will benefit, and adding this therapy over the course of a patient’s entire disease adds further toxicity. ■

DISCLOSURE: Dr. Gubens is a consultant for AbbVie, AstraZeneca, BMS, Genentech/Roche, Mersana, and Novartis; and has received institutional honoraria for contracted research from Celgene, Merck, Novartis, OncoMed, and Roche. 

REFERENCES 

1. Gubens M: Lung cancer. Best of ASCO New Orleans. Presented July 29, 2017

2. Brahmer J, et al: 2017 ASCO Annual Meeting. Abstract 9000. Presented June 6, 2017

3. Reck M, et al: N Engl J Med 375:1823-1833, 2016. 

4. Peters S, et al: J Thorac Oncol 11(4 suppl):S139-S140, 2016. 

5. Bennouna J, et al: 2017 ASCO Annual Meeting. Abstract 9004. Presented June 6, 2017.



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