Novel patterns of progression upon immunotherapy in other thoracic malignancies and uncommon populations

Our plain-English summary of Novel patterns of progression upon immunotherapy in other thoracic malignancies and uncommon populations, by R. Ferrara, D. Signorelli, C. Proto, et al (Translational Lung Cancer Research, 2021).

The study

• Authors: R. Ferrara, D. Signorelli, C. Proto, A. Prelaj, M.C. Garassino, G. Lo Russo
• Journal: Translational Lung Cancer Research
• Published: 2021;10(6):2955-2969
• Type of article: Review
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

In the immunotherapy era, considering the prolonged survival benefit and responses observed with immunecheckpoint inhibitors (ICI) in many cancer types, the identification of patients with rapid progression (PD) and deaths upon ICI has found some skepticism and resistance among the scientific community. Nevertheless, an acceleration of tumour during ICI, defined as hyperprogressive disease (HPD), has been recognized across different cancer types and evidence regarding rapid PDs and deaths are emerging in patients with malignant pleural mesothelioma (MPM), small cell lung cancer (SCLC) and thymic malignancies and in uncommon non-small cell lung cancer (NSCLC) populations. Of note, PD and early deaths (ED) rates upon single agent ICI were up to 60% and 30% in MPM and 70% and 38% in SCLC patients, respectively. Similarly, rapid PDs and deaths were observed in clinical trials and retrospective studies including patients with poor performance status (PS), HIV infection and rare NSCLC histologies. Atypical patterns of response, such as pseudoprogression (PsPD) may also occur in other thoracic malignancies (MPM) and in some uncommon populations (i.e., HIV patients), however probably at lower rate compared to HPD. The characterizations of HPD and PsPD mechanisms and the identification of common definition criteria are the next future challenges in this area of cancer research.

2021 Translational Lung Cancer Research. All rights reserved.

In plain English

This article was a literature review, not a new study. The authors searched PubMed, the Cochrane Library and EMBASE for published reports on immune checkpoint inhibitors, a type of immunotherapy drug. They focused on malignant pleural mesothelioma, small cell lung cancer, thymic tumours and uncommon groups of non-small cell lung cancer patients. They looked at two unusual patterns: hyperprogression, a rapid speeding-up of tumour growth during treatment, and pseudoprogression, apparent growth later followed by shrinkage. The article did not discuss asbestos exposure. Across the mesothelioma trials they reviewed, the authors reported progression rates from 15% up to 60% and early death rates from 9% up to 30%. In one mesothelioma trial (MAPS-2), hyperprogression was found in 6 of 125 patients by one definition and 11 of 125 by another. They put pseudoprogression in mesothelioma at 2 to 9%. The authors concluded that evidence of rapid progression and early deaths is emerging in these cancers and groups. They judged that pseudoprogression probably occurs less often, and that common definitions are still needed. They noted there is no agreed definition of hyperprogression.

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: Narrative literature review of published clinical trials, retrospective studies and a meta-analysis
• Who was studied: Published studies of patients treated with immune checkpoint inhibitors who had malignant pleural mesothelioma (MPM), small cell lung cancer (SCLC), thymoma or thymic carcinoma, or belonged to uncommon non-small cell lung cancer groups (elderly patients, poor performance status, autoimmune diseases, HIV infection, rare histology). Sources were found in PubMed, the Cochrane Library and EMBASE, with no language or period restrictions. The search date is not given.
• Exposure: Immune checkpoint inhibitor drugs, given alone or combined with each other or with chemotherapy: anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies (e.g. nivolumab, pembrolizumab, avelumab, durvalumab, atezolizumab, tremelimumab, ipilimumab). No asbestos or fiber exposure is discussed.
• Main results:
  • Across the pretreated MPM clinical trials reviewed, progression rates ranged from 15% up to 60% and early death rates from 9% up to 30%. The authors said this, together with the MAPS-2 analyses, suggests hyperprogression also occurs in pretreated MPM.
  • In the MAPS-2 MPM trial, hyperprogression defined by tumour growth rate was found in 6 (5%) of 125 patients: 4 in the nivolumab arm and 2 in the nivolumab plus ipilimumab arm.
  • In MAPS-2, hyperprogression defined by tumour growth kinetics was reported in 11 (9%) of 125 MPM patients.
  • In MAPS-2, MPM patients with conventional progression had a median overall survival of 5.5 months (95% CI: 2.6 to 8.9). Patients with hyperprogression (tumour growth kinetics definition) had 2.6 months (95% CI: 0.8 to 7.7). The hazard ratio was 0.37 (95% CI: 0.19 to 0.75), P=0.006.
  • In MAPS-2, hyperprogression was significantly associated with negative PD-L1 expression (less than 1%) on tumour cells. Of the 11 patients with hyperprogression, 8 had negative PD-L1 expression.
  • In the Checkmate 743 MPM trial (nivolumab plus ipilimumab vs cisplatin and pemetrexed), early death rates in the immunotherapy arm were:
• overall: 10% (30/303)
• epithelioid histology: 10% (22/229)
• sarcomatoid histology: 11% (8/74)
  In the chemotherapy arm they were 11% (34/302), 10% (23/227) and 15% (11/75).
  • Pseudoprogression in MPM was rare, reported at 2 to 9%. In the Dutch nivolumab trial, 3 (9%) of 34 MPM patients had it.
  • In MPM, pseudoprogression was associated with worsening of clinical condition. The authors described this as peculiar to MPM, so clinical evaluation did not help tell it apart from true progression.
  • In SCLC trials, progression rates ranged from 6% to 70% and early death rates from 6% up to 38%. The authors said hyperprogression in SCLC could not be excluded.
  • In thymic malignancies, the authors judged that striking or rapid progressions with deaths, although rare, may occur with single-agent immunotherapy.
• The authors' conclusion: The authors concluded that evidence of rapid progression and early deaths during immunotherapy is emerging for MPM, SCLC, thymic carcinoma and several uncommon patient groups. They judged that pseudoprogression may also occur in MPM and HIV patients, but probably at a lower rate than hyperprogression. They said understanding the mechanisms and agreeing common definitions are the next challenges.
• Limitations the authors state:
  • There is no consensus on how to define hyperprogression, and different criteria have been proposed.
  • Hyperprogression has been shown only in retrospective studies, because defining it requires imaging from before treatment, which clinical trials did not collect.
  • Progression and early death rates give only a rough estimate of hyperprogression. Early death rates may also include deaths from drug toxicity.
  • The tumour growth rate method treats tumours as spheres. Mesothelioma rarely has a spherical shape, so the method is hard to apply.
  • There is no standard definition of pseudoprogression.

Topics

Medical terms in this study, explained in our Lexicon: Immunotherapy, Pleural Mesothelioma, Small Cell Lung Cancer, Non-Small Cell Lung Cancer, Clinical Trial, Performance Status.

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