Efficacy of Immune Checkpoint Inhibitors in Rare Tumours: A Systematic Review

Our plain-English summary of Efficacy of Immune Checkpoint Inhibitors in Rare Tumours: A Systematic Review, by F. Petrelli, F. Consoli, A. Ghidini, et al (Frontiers in Immunology, 2021).

The study

• Authors: F. Petrelli, F. Consoli, A. Ghidini, G. Perego, A. Luciani, P. Mercurio, A. Berruti, S. Grisanti
• Journal: Frontiers in Immunology
• Published: 2021;12:720748
• Type of article: Meta-analysis, Systematic review
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Rare cancers, as defined by the European Union, occur in fewer than 15 out of 100,000 people each year. The International Rare Cancer Consortium defines rare cancer incidence as less than six per 100,000 per year. There is a growing number of reports of the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with rare tumours, and hence, we conducted a comprehensive review to summarise and analyse the available literature.

Methods: A literature search of PubMed was performed on January 31, 2021, using the following ICI names as keywords: ipilimumab, tremelimumab, cemiplimab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab. Studies on patients with rare tumours who were being treated with ICIs were included. We plotted the overall response rate against the corresponding median survival across a variety of cancer types using linear regression.

Results: From 1,255 publications retrieved during the primary search, 62 publications were selected (with a total of 4,620 patients). Only four were randomised trials. A minority were first-line studies, while the remaining were studies in which ICIs were delivered as salvage therapy in pretreated patients. There was a good correlation between response rate and overall survival (Spearman R2 >0.9) in skin cancers, mesothelioma, and sarcomas.

Conclusions: Treatment of advanced-stage rare tumours with ICI therapy was found to be associated with significant activity in some orphan diseases (e.g., Merkel cell carcinoma) and hepatocellular carcinoma. Several ongoing prospective clinical trials will expand the knowledge on the safety and efficacy of ICI therapy in patients with these rare cancers.

Copyright © 2021 Petrelli, Consoli, Ghidini, Perego, Luciani, Mercurio, Berruti and Grisanti.

In plain English

This article was a systematic review of published trials, not a new study of patients. The authors searched the medical literature on January 31, 2021, for trials of immune checkpoint inhibitors (drugs including nivolumab, ipilimumab, pembrolizumab, durvalumab and tremelimumab) in patients with advanced rare solid cancers. They included 62 of 1,255 publications, covering 4,620 patients. Most were phase 2 trials in previously treated patients. Thirteen studies concerned rare thoracic tumours, mainly mesothelioma, including eight phase 2 trials with 734 patients with pleural mesothelioma. The review did not examine asbestos exposure. Response rates across all cancers ranged from 0% to 60%. Comparing studies that reported both response rate and overall survival (the article says only 43 studies had both), the authors reported a Spearman correlation of 0.69 between the two, and an R2 of 0.97 for mesotheliomas. They concluded that these drugs offer significant clinical benefit in some conditions, such as hepatocellular carcinoma, non-melanoma skin cancers and Merkel cell carcinoma, but that efficacy in other rare tumours could not be fully ascertained. They noted few randomised trials and missing biomarker data.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Systematic review of published clinical trials, following the PRISMA reporting guideline, with descriptive statistics and a linear regression of overall survival against overall response rate
• Who was studied: 62 publications (out of 1,255 retrieved), published between 2013 and 2021, including 4,620 patients with advanced rare solid tumours. The tumours were skin cancers (14 studies), rare thoracic tumours, mainly mesothelioma (13), endocrine malignancies (11), hepatobiliary cancers (10), sarcomas (9), testicular cancers (3) and salivary gland tumours (2).
• Exposure: Treatment with immune checkpoint inhibitors (ipilimumab, tremelimumab, cemiplimab, nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab), alone or combined with other agents, for advanced-stage rare solid cancers. Asbestos exposure was not studied.
• Main results:
  • Eight phase 2 trials with a total of 734 patients evaluated immune checkpoint inhibitors in pleural mesothelioma (MPM). Only two of these trials used them as first-line treatment.
  • In pleural mesothelioma, durvalumab plus cisplatin and pemetrexed was reported with an overall response rate of 48% and an overall survival of 18.4 months.
  • The authors reported that a phase 3 trial established nivolumab plus ipilimumab as a potential new standard of care for previously untreated pleural mesothelioma. Their table lists 713 patients, with median overall survival of 18.1 months versus 14.1 months with chemotherapy.
  • Across all groups of rare cancers, the overall response rate ranged from 0% to 60%, with a median of 20%.
  • The correlation between overall response rate and overall survival, measured across studies, had a Spearman coefficient of 0.69. The authors interpreted this as meaning that about 70% of outcomes could be driven by tumour response.
  • The article states that data on both overall survival and overall response rate were available in only 43 studies.
  • By disease group, the response–survival correlation was R2 = 0.98 for skin cancers, R2 = 0.97 for mesotheliomas, R2 = 0.93 for sarcomas, R2 = 0.65 for endocrine neoplasms, and R2 = −0.14 for hepatobiliary cancers.
  • Used as first-line treatment, immune checkpoint inhibitors gave overall response rates above 40% in cutaneous squamous cell carcinoma and 60% in Merkel cell carcinoma.
  • In hepatocellular carcinoma after sorafenib failure, at least four phase 2 studies of pembrolizumab and nivolumab showed a mean overall response rate of about 20% (range 18 to 22%), median progression-free survival of 4.5 months (range 3 to 6.9) and median overall survival of 12.2 months (range 8.2 to 13.9).
  • In nine phase 2 studies of 324 patients with advanced pretreated sarcomas, responses were rare overall and median progression-free survival was approximately 1 to 2 months.
• The authors' conclusion: The authors concluded that, for some conditions (hepatocellular carcinoma, non-melanoma skin cancers and Merkel cell carcinoma), treatment with immune checkpoint inhibitors offers significant clinical benefit. In other rare tumours, they said efficacy cannot be fully ascertained because the trials were small and non-randomised.
• Limitations the authors state:
  • Only a few randomised studies compared these drugs with standard treatments, so a direct comparison was not possible.
  • Many confirmatory phase 3 studies were still ongoing and were not included.
  • Many trials lacked information on predictive biomarkers.
  • Small sample sizes and non-randomised trial designs meant efficacy in many rare tumours could not be fully ascertained.

Topics

Medical terms in this study, explained in our Lexicon: checkpoint inhibitors, Systematic Review, Ipilimumab (Yervoy), Tremelimumab, Nivolumab (Opdivo), Pembrolizumab (Keytruda), Atezolizumab (Tecentriq), Durvalumab (Imfinzi).

Related studies

• Safety and efficacy of PD-1/PD-L1 immune checkpoint inhibitors in patients with pre-treated advanced stage malignant mesothelioma: a systematic review and meta-analysis — A. Zafar, A.A. Rashid, et al. (2024)
• Efficacy and safety of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors in the treatment of diffuse pleural mesothelioma: a systematic review and meta-analysis — P. Sun, D. Song, et al. (2025)
• Comparative efficacy of immune checkpoint inhibitors versus chemotherapy alone in diffuse pleural mesothelioma — X. Zhang, L. Chang, et al. (2024)
• Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy — J. Harber, T. Kamata, et al. (2021)
• Celiac Disease After Administration of Immune Checkpoint Inhibitors: A Case Report — J. Leblanc, S. Hoibian, et al. (2021)
• Efficacy of nivolumab and ipilimumab in patients with malignant pleural mesothelioma is related to a subtype of effector memory cytotoxic T cells: Translational evidence from two clinical trials — J.M. Mankor, M.J. Disselhorst, et al. (2020)

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