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Ipilimumab shows promise in mutated NSCLC, but toxicities may limit use
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CHICAGO — The addition of ipilimumab to targeted therapy for the treatment of EGFR- and ALK-mutated non-small cell lung cancer demonstrated improved survival despite dose-dependent toxicities, according to results from a phase 1b trial presented at the International Association for the Study of Lung Cancer Multidisciplinary Symposium in Thoracic Oncology.
Ipilimumab (Yervoy, Bristol-Myers Squibb), a CTLA-4 inhibitor, has demonstrated long-term responses in patients with melanoma; however, the drug is associated with a high rate of grade 3 and grade 4 immune-related adverse events.
In NSCLC, results following treatment with ipilimumab appeared to be modest, Anna Chalmers, MD, clinical instructor in the division of oncology at University of Utah and an investigator at Huntsman Cancer Institute, said during the presentation.
“EGFR- and ALK-positive lung cancer has a longer OS and PFS on targeted frontline therapy compared with wild-type [disease],” she added. “However, patients who are EGFR mutated and nonsmokers are known to have a decreased response to anti-PD-1 therapy. ... Therefore, there is an opportunity and a need to improve the effectiveness of immunotherapy in this patient population.”
Chalmers and colleagues evaluated the efficacy and safety of ipilimumab in combination with erlotinib (Tarceva, Genentech), an EGFR-targeted therapy, or crizotinib (Xalkori, Pfizer), an ALK and ROS1 inhibitor, in patients with EGFR- or ALK-mutated NSCLC.
Patients received 3 mg/kg ipilimumab every 3 weeks for four cycles, plus erlotinib or crizotinib at their tolerated dose until disease progression.
Of the six initial patients with EGFR-mutated NSCLC, two patients recorded a dose-limiting toxicity caused by grade 3 to grade 4 diarrhea.
As a result, researchers amended the protocol to accrue an additional 10 patients treated at reduced dose of 1 mg/kg ipilimumab to better characterize toxicity and treatment interaction.
However, due to excessive toxicity, researchers closed the study after enrolling 14 patients (EGFR, n = 11; ALK, n = 3).
Researchers administered a median of four doses.
Of the 11 patients with EGFR mutations, four developed grade 3 to grade 4 diarrhea, which required steroids and infliximab therapy.
Of the three patients with ALK mutations, one developed grade 3 hypophysitis and another patient experienced grade 2 pneumonitis.
All 14 patients recovered from toxicity, except one patient who required chronic steroid replacement.
No treatment-related deaths occurred.
Patients with EGFR-mutated NSCLC demonstrated a median PFS of 17.9 months — three patients had not progressed at a follow-up of 44.7 months — and a median OS of 38 months.
Patients with ALK-mutated NSCLC demonstrated a median PFS of 24.1 months — one patient had not progressed after 45 months of follow-up — and a median OS of 41.6 months.
“The combination of targeted therapy with ipilimumab led to prolonged PFS and OS,” Chalmers said. “While this is a very small trial, the PFS exceeding 2 years vs. the anticipated PFS of close to 1 year is promising and further study is warranted.” – by Kristie L. Kahl
Reference:
Chalmers A, et al. Abstract OA02.02. Presented at: International Association for the Study of Lung Cancer Multidisciplinary Symposium in Thoracic Oncology; Sept. 14-16, 2017; Chicago.
Disclosure: The trial was funded by Bristol Myers-Squibb. Chalmers reports no relevant financial disclosures.
Perspective
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Hossein Borghaei, DO, MS
The efficacy data are very interesting. This is not a randomized study, which makes it a little bit weaker. The numbers are small, contributing to the difficulty in knowing what we are dealing with. Clearly, with a higher rate of the toxicity, I would question the use of ipilimumab. That is usually associated with a higher risk for toxicity, so perhaps a different checkpoint inhibitor would be more appropriate.
The bigger question: Now that we have more targeted therapies for this patient population, is there really a need to get everyone on immunotherapy? I don’t think we are necessarily obligated to offer immunotherapy to every single patient with lung cancer with different molecular subtypes. There are different options for these patients. As long as we don’t understand the biology of what is going on with this interaction, I’m not in favor of trying these combinations again until we have a better understanding of the impact.
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