According to Dr Borghaei, immunotherapies may offer a great deal of promise and have an “acceptable” side effect profile. “There is not much change in blood counts, although that could happen. But what we do see is immune-related side effects such as colitis, pneumonitis, hypothyroidism and some hyperthyroidism. The incidence of these events with single agent anti PD-1 drugs is low. There are combination studies with an anti-PD-1 and a CTLA-4 antibody that do report higher toxicities than single-agent trials.”

David Gerber, MD, associate professor, division of hematology-oncology, and associate director for clinical research at the University of Texas Southwestern Medical Center in Dallas, said it’s important to note that a number of characteristics make SCLC (15% of lung cancer cases) distinct from NSCLC (85% of lung cancer cases). “For initial treatment, the vast majority of patients respond to chemotherapy. Approximately 80% respond, which is more than twice the response rate typically seen in NSCLC. Once the cancer has progressed, however, very few patients respond to second-line chemotherapy, with response rates lower than that seen with second-line chemotherapy for NSCLC.”


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There are a number of characteristics suggesting that SCLC patients would derive particular benefit from immunotherapy. Almost all patients with SCLC are current or prior smokers; smoking increases the number of mutations in a cancer, which probably increase the antigenicity of the cancer, potentially making the cancer more responsive to immunotherapy.

“Independent of treatment, SCLC is an immunogenic cancer, which is evidenced by a high rate of autoimmune paraneoplastic conditions in patients with SCLC. Autoimmune paraneoplastic conditions, which most commonly affect the nervous system, occur because the patient’s immune system forms antibodies against the SCLC that cross-react with normal tissues and organs,” said Dr Gerber.

Despite these characteristics, initial reports do not suggest that the benefit of immunotherapy is any greater than that seen in NSCLC. Clinical development of immunotherapy in SCLC may differ from that in NSCLC in a number of ways, according to Dr Gerber: “for instance, there have already been clinical trials in which immunotherapy is compared directly to chemotherapy as first-line treatment of advanced NSCLC. Given the high efficacy rates of chemotherapy for first-line treatment of SCLC, we are unlikely to see trials substituting immunotherapy for chemotherapy in that setting in the near future.”

According to Dr Gerber, immunotherapy represents 1 of the greatest advances in cancer therapy in the past 30 years. For some patients, responses to immunotherapy appear to last longer than do responses to molecularly targeted therapies or to chemotherapy, suggesting that some patients may achieve long-term survival.

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He cautions, however, that while immunotherapy may cause fewer adverse effects and be associated with better quality of life than chemotherapy, a minority of patients experience immune-related toxicities. “These events are unpredictable, potentially severe, and possibly permanent. They are distinct from the toxicities of chemotherapy and molecularly targeted therapies, so medical oncologists and other physicians are having to learn how to diagnose and treat them effectively in a timely fashion. While combination immune therapy regimens appear in some cases to be more effective than single-agent immunotherapy, they also convey more toxicity,” said Dr Gerber.

Immunotherapy will probably become part of the standard of care for SCLC in the coming years, though it remains to be seen whether it will be used only for extensive or limited stage disease, and whether it will be used for first- or second-line therapy.

References

  1. Horn L, Reck M, Spigel DR. The future of immunotherapy in the treatment of small cell lung cancer. Oncologist. 27 Jun 2016. doi: 10.1634/theoncologist.2015-0523 [Epub ahead of print]
  2. Pietanza C, Sigel DR, Baure T et al. Safety, activity, and response durability assessment of single agent rovalpituzumab tesirine, a delta-like protein3 (DLL3)-targeted antibody drug conjugate (ADC), in small cell lung cancer (SCLC). Paper presented at: 40th Congress of the European Society for Medical Oncology (ESMO); September 2015; Vienna, Australia.