Combination ICI regimens are also being reviewed.2,9 Ongoing studies are, for example, evaluating ICIs combined with chemotherapy and radiotherapy in patients with NSCLC, for example.1,2

Combined treatment with durvalumab and tremelimumab (a PD-L1-targeting ICI and an anti-CTLA-4 agent, respectively) showed early promise against advanced NSCLC in an early-phase clinical trial but, in phase 3 testing, the combination did not improve PFS among patients with tumors expressing PD-L1 at an intermediate level.10


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Yet while many patients with NSCLC benefit from ICIs, there remain important unanswered questions about efficacy and safety for different patient subgroups.

Most clinical trials exclude patients with autoimmune disease and brain metastases, noted Jordi Remon, MD, a medical oncologist at Hospital Vall d’Hebron in Barcelona, Spain, and coauthors.7 The potential benefits and risks of ICIs for elderly or fragile patients are unclear for the same reason.

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The “brain is one of the most common metastatic sites of NSCLC,” the authors stated.7 Nearly a third of patients experience brain metastasis, and half already have a brain metastasis by the time their primary cancer is diagnosed.

Up to 52% of patients with brain metastases have PD-L1-positive metastases (at least 5% using the E1L3N antibody test), which is higher than in matched primary lung tumors. There are preliminary suggestions from small, early-phase clinical trials of ICI treatment in melanoma that nivolumab with or without ipilimumab might improve PFS among patients with brain metastases.7

Dr Remon and colleagues called for inclusion of patients with NSCLC and brain metastases in clinical trials of ICIs.

Thirteen to 14% of patients with NSCLC also have an autoimmune disease, but these patients and patients on steroid therapy are usually excluded from clinical ICI trials, in part because corticosteroids can be immunosuppressive and might antagonize immunotherapy efficacy.7 Yet the available clinical evidence suggests that relatively few of these patients experience worsening autoimmune symptoms on ICIs.

The safety of ICIs in patients with more severe or symptomatic baseline autoimmune disease has, however, been too little-studied to draw any firm conclusions about safety, so when these patients are treated with ICIs, they should be very closely monitored. Optimal dosing and retreatment after ICI-associated toxicity also require further study.

Antibiotics are another “burning question” about patient selection for ICIs, Dr Remon and colleagues noted.7 Antibiotics that affect gut microbiome ecology appear to diminish ICI efficacy.11

“Expanded access programs in the real-world setting are warranted to shed more light into the real benefit and safety of ICIs in special subgroups of NSCLC patients,” the authors said.7 “Meanwhile, treatment decisions in these special situations…must be individualized and taken with caution.”

References

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  2. Somasundaram A, Burns TF. The next generation of immunotherapy: keeping lung cancer in check. J Hematol Oncol. 2017;10(1):87.
  3. NCI dictionary of cancer terms: immune checkpoint inhibitor. National Cancer Institute website. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immune-checkpoint-inhibitor. Accessed March 2018.
  4. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106.
  5. Herzberg B, Campo MJ, Gainor JF. Immune checkpoint inhibitors in no-small cell lung cancer. Oncologist. 2017;22(1):81-8. doi: 10.1634/theoncologist.2016-0189
  6. Assi H, Kamphorst AO, Moukalled NM, Ramalingam SS. Immune checkpoint inhibitors in advanced non-small cell lung cancer. Cancer. 2018;124(2):248-61. doi: 10.1002/cncr.31105
  7. Remon J, Vilariño N, Reguart N. Immune checkpoint inhibitors in non-small cell lung cancer (NSCLC): approaches on special subgroups and unresolved burning questions. Cancer Treat Rev. 2018;64:21-9. doi: 10.1016/j.ctrv.2018.02.002
  8. Remon J, Besse B, Soria JC. Successes and failures: what did we learn from recent first-line treatment immunotherapy trials in non-small cell lung cancer? BMC Med. 2017;15:55. doi: 10.1186/s12916-017-0819-3
  9. Tanvetyanon T, Gray JE, Antonia SJ. PD-1 checkpoint blockade alone or combined PD-1 and CTLA-4 blockade as immunotherapy for lung cancer? Exp Opin Biol Ther. 2017;17(3):305-12.
  10. Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumor activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17(3):299-308.
  11. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2017 Nov 2. doi:10.1126/science.aan3706 [Epub ahead of print]