Combining immunotherapy with chemotherapy, molecular therapy, or anti-angiogenic therapy has shown promising results in recent randomized trials of patients with lung cancer, although none of the combinations have yet to demonstrate clear superiority, according to Paul A. Bunn Jr, MD, Distinguished Professor and chair of Lung Cancer Research at University of Colorado Cancer Center. Bunn presented his recent findings at the 2016 International Lung Cancer Congress.
Bunn summarized results from the CheckMate-012 trial (NCT01454102), in which treatment-naïve patients with advanced non–small cell lung cancer (NSCLC) received nivolumab (Opdivo) alone or in combination with other therapies. Similar to previous studies in melanoma, the combination of ipilimumab (Yervoy) plus nivolumab tended to yield a better response than nivolumab monotherapy, particularly in patients with high PD-L1 expression. The addition of platinum-based doublet chemotherapy led to variable response rates (33%-47%) that were slightly higher than chemotherapy alone, along with overall survival (OS) rates ranging from 50% to 87%. Although this study is still ongoing, Bunn predicted that the results will be instrumental for prescribing therapies in the near future based on PD-L1 expression and histologic type of the tumor.
The CheckMate-227 trial (NCT02477826) tested tumor PD-L1 status for treatment-naïve patients with stage IV or recurrent NSCLC. Patients with PD-L1–positive tumors were stratified to receive nivolumab monotherapy, nivolumab plus ipilimumab, or platinum-based doublet chemotherapy, whereas the PD-L1–negative group received nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone.
Bunn noted that the trial could be “potentially game-changing,” and noted that even the PD-L1–negative group appeared to benefit substantially from combination therapy. Other ongoing trials of combination therapy in the first-line setting include the MYSTIC and NEPTUNE trials, which compare the efficacy of durvalumab plus tremelimumab with standard of care and, in the MYSTIC trial, durvalumab monotherapy.
Although adding chemotherapy to anti–PD-1 therapy may intuitively yield a superior response over nivolumab alone, Bunn indicated that some studies—while small—do not readily confirm this. Bunn compared 2 separate studies and showed that for advanced NSCLC, nivolumab combined with platinum-based doublet chemotherapies did not produce an “obvious” benefit in OS over nivolumab alone. Other studies investigated atezolizumab (Tecentriq) in combination with various platinum-based doublet chemotherapies and showed that the majority of patients with NSCLC had a partial or complete response, although the number of patients on each regimen was small, from 8 to 16.
Bunn noted that early data on combination therapy for small cell lung cancer (SCLC) might be particularly noteworthy because this form of lung cancer tends to have a notably short response duration to chemotherapy alone. The CheckMate-0321
trial of patients with SCLC showed the overall response rate was 31% in the group receiving nivolumab plus ipilimumab and approximately 13% in the group receiving nivolumab monotherapy, and the group with the combined therapy tended to have improved OS.
Additionally, Bunn noted that the response rate to combined therapy in CheckMate-032, which included patients regardless of PD-L1 status, was similar to the response rate (35%) to pembrolizumab (Keytruda) in the phase Ib KEYNOTE-028 trial of patients with SCLC and ≥1% PD-L1 expression in tumor or tumor-infiltrating immune cells and that, unlike the short duration of response to chemotherapy, responses to the combination immunotherapy appeared durable. “Even though these response rates of 30% to 31% are not overwhelming, these responses really do last a long time,” said Bunn.
Anti-angiogenic agents may be synergistic with immunotherapies, Bunn stated, because of their immunomodulatory properties, including increases in T-cell trafficking into tumors and reducing suppressive cytokines, infiltrating regulatory T cells, and myeloid-derived suppressor cells. Preclinical data in mice models suggested that combination of anti-angiogenic agents with immunotherapy may be beneficial, and ongoing clinical trials in humans are investigating combinations of anti–PD-1 agents with bevacizumab (Avastin).
In his experience, Bunn noted that PD-L1 expression and response rates to PD-1/PD-L1 inhibitors tends to be lower in patients with molecular driver mutations. Nevertheless, several ongoing phase I trials are showing promising responses to combination therapy, although he cautioned that tumor shrinkage is expected in patients with driver mutations receiving the appropriate molecular therapy and that early response may not predict long-term outcome.
Combination therapy with multiple immune checkpoint inhibitors or immune stimulants is undergoing investigation in early phase I/II trials. However, Bunn stated that the current data are insufficient to predict which of these combinations will prove effective or whether one particular combination is superior to another. Moreover, he predicted that the combination of PD-1/PD-L1 inhibitors with CTLA-4 antibodies would be among the most effective and least toxic, whereas the combinations involving chemotherapy or molecular therapy will be more toxic and not provide additional benefit over sequential administration of the 2 agents.