Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma

Abstract

The anti-PD-1 antibodies nivolumab and pembrolizumab are active in metastatic melanoma; however, there is limited data on combining anti-PD-1 antibody and radiotherapy (RT). We sought to review clinical outcomes of patients receiving RT and anti-PD-1 therapy. All patients receiving anti-PD-1 antibody and RT for metastatic melanoma were identified. RT and systemic treatment, clinical outcome, and toxicity data were collected. Fifty-three patients were included; 35 patients received extracranial RT and/or intracranial stereotactic radiosurgery (SRS) and 21 received whole brain radiotherapy (WBRT) (three of whom also received SRS/extracranial RT). Patients treated with extracranial RT or SRS received treatment either sequentially (RT then anti-PD-1, = 11), concurrently ( = 16), or concurrent "salvage" treatment to lesions progressing on anti-PD-1 therapy ( = 15). There was no excessive anti-PD-1 or RT toxicity observed in patients receiving extracranial RT. Of six patients receiving SRS, one patient developed grade 3 radiation necrosis. In 21 patients receiving WBRT, one patient developed Stevens-Johnson syndrome, one patient developed acute neurocognitive decline, and one patient developed significant cerebral edema in the setting of disease. Response in irradiated extracranial/intracranial SRS lesions was 44% for sequential treatment and 64% for concurrent treatment (=0.448). Likewise there was no significant difference between sequential or concurrent treatment in lesional response of non-irradiated lesions. For progressing lesions subsequently irradiated, response rate was 45%. RT and anti-PD-1 antibodies can be safely combined, with no detectable excess toxicity in extracranial sites. WBRT and anti-PD-1 therapy is well tolerated, although there are rare toxicities and the role of either anti-PD-1 or WBRT in the etiology of these is uncertain.

Safety of combined PD‐1 pathway inhibition and radiation therapy for non‐small‐cell lung cancer: A multicentric retrospective study from the GFPC

“…According to our restricted mean survival analysis, the therapeutic sequence (radiotherapy before nivolumab vs. radiotherapy during/after nivolumab) did not impact outcomes. Similar conclusions were drawn based on a cohort of 53 melanoma patients treated with radiotherapy and anti‐PD‐1 (nivolumab or pembrolizumab) . Neither response rates nor OS differed between patients given concurrent or sequential radiotherapy.…”

Immuno-oncology Clinical Trial Design: Limitations, Challenges, and Opportunities

“…A phase I/II study assessing ipilimumab with or without XRT (a single 8 Gy dose to focal bony lesions, <3 lesions 24–48 hours prior to ipilimumab dose) in hormone-resistant prostate cancer did not demonstrate any increased toxicity with combination therapy (24). Similarly, retrospective data from 53 advanced melanoma patients receiving extracranial and/or intracranial XRT concurrently with an anti-PD1 antibody also demonstrated no excess toxicities with extracranial XRT; however, neurologic AEs such as severe radiation necrosis, acute neurocognitive decline and cerebral edema were seen with intracranial XRT (25). Studies vary as to whether concurrent intracranial XRT and ICI are associated with excess neurologic AEs (26) or not (27) and remains an active area of investigation (28).…”

The Role of Radiation Oncology in Immuno-Oncology

“…In a study of a small sample, patients with metastatic melanoma were treated with extracranial RT or SRS in combination either sequentially (RT then anti‐PD‐1, n = 11) or concurrently ( n = 16), or with salvage RT for lesions progressing while the patient was treated with anti‐PD‐1 therapy (anti‐PD‐1 then RT, n = 15). No significant difference in the response was observed between the concurrent and sequential cohorts . Ahmed et al retrospectively analyzed patients receiving nivolumab and SRS using two nivolumab protocols: NCT01176461 and NCT01176474.…”

“…In a phase I study, 11 of 16 patients receiving ipilimumab and radiotherapy reported grade 3 toxicities . Radiation‐induced necrosis was observed in patients receiving treatment for melanoma metastasis to the brain . Moreover, two patients with NSCLC developed nivolumab‐induced radiation recall pneumonitis that exactly matched the irradiated field after the administration of 60 Gy of thoracic RT .…”