Analysis of Cancer Survival Associated With Immune Checkpoint Inhibitors After Statistical Adjustment

Abstract

ImportanceAppropriate clinical decision-making relies on accurate data interpretation, which in turn relies on the use of suitable statistical models. Long tails and early crossover—2 features commonly observed in immune checkpoint inhibitor (ICI) survival curves—raise questions as to the suitability of Cox proportional hazards regression for ICI survival analysis. Cox proportional hazards–Taylor expansion adjustment for long-term survival data (Cox-TEL) adjustment may provide possible solutions in this setting.ObjectiveTo estimate overall survival and progression-free survival benefits of ICI therapy vs chemotherapy using Cox-TEL adjustment.Data SourcesA PubMed search was performed for all cataloged publications through May 22, 2022.Study SelectionThe search was restricted to randomized clinical trials with search terms for ICIs and lung cancer, melanoma, or urothelial carcinoma. The publications identified were further reviewed for inclusion.Data Extraction and SynthesisCox proportional hazards ratios (HRs) were transformed to Cox-TEL HRs for patients with short-term treatment response (ie, short-term survivor) (ST-HR) and difference in proportions for patients with long-term survival (LT-DP) by Cox-TEL. Meta-analyses were performed using a frequentist random-effects model.Main Outcomes and MeasuresOutcomes of interest were pooled overall survival (primary outcome) and progression-free survival (secondary outcome) HRs, ST-HRs, and LT-DPs. Subgroup analyses stratified by cancer type also were performed.ResultsA total of 1036 publications was identified. After 3 levels of review against inclusion criteria, 13 clinical trials (7 in non–small cell lung cancer, 3 in melanoma, and 3 in urothelial carcinoma) were selected for the meta-analysis. In the primary analysis, pooled findings were 0.75 (95% CI, 0.70-0.81) for HR, 0.86 (95% CI, 0.81-0.92) for ST-HR, and 0.08 (95% CI, 0.06-0.10) for LT-DP. In the secondary analysis, the pooled values for progression-free survival were 0.77 (95% CI, 0.64-0.91) for HR, 1.02 (95% CI, 0.84-1.24) for ST-HR, and 0.10 (95% CI, 0.06-0.14) for LT-DP.Conclusions and RelevanceThis systematic review and meta-analysis of ICI clinical trial results noted consistently larger ST-HRs vs Cox HRs for ICI therapy, with an LT-DP of approximately 10%. These results suggest that Cox HRs may not provide a full picture of survival outcomes when the risk reduction from treatment is not constant, which may aid in the decision-making process of oncologists and patients.

Immunosurveillance in clinical cancer management

“…89,119 Although the percentage of patients suffering from other cancers that respond to ICIs can be sizeable (usually 15%-25% of patients), it is still too early to claim long-term benefits (e.g., >10 years) or definitive cures beyond anecdotal cases in such indications because of the short follow-up. 23 Contemporary research is focusing on the distinction between primary (innate) resistance and secondary (acquired) ICI resistance. 120 In the former setting, the goal is to provide treatment with ICIs only to patients who are predicted to respond by a clinical or molecular biomarker or to subvert the initial mechanism of resistance.…”

“…This has been dramatically achieved in patients with melanoma and RCC who received PD‐1 inhibitors alone or combined with ipilimumab, 117,118 as well as in patients with NSCLC who received chemotherapy plus pembrolizumab or nivolumab 89,119 . Although the percentage of patients suffering from other cancers that respond to ICIs can be sizeable (usually 15%–25% of patients), it is still too early to claim long‐term benefits (e.g., >10 years) or definitive cures beyond anecdotal cases in such indications because of the short follow‐up 23 …”

“…17 That said, even locally invasive and metastatic cancers may respond to ICIs, demonstrating the possibility to reverse the natural progression of the disease and reestablish equilibrium. 23 Here, we review prognostic and predictive biomarkers related to anticancer immunosurveillance and emphasize the finding that successful cancer treatments, including chemotherapeutics, radiation therapy (RT), and some targeted agents, operate (at least partially) through the immune system. Moreover, we summarize the state-ofthe-art of immunotherapy, alone or in combination with other treatment modalities, placing special emphasis on preoperative treatment in the context of operable disease.…”

“…However, once cancers progress or spread (the escape phase), the probability of achieving durable or at least clinically relevant responses to any treatment diminishes 17 . That said, even locally invasive and metastatic cancers may respond to ICIs, demonstrating the possibility to reverse the natural progression of the disease and reestablish equilibrium 23 …”

Exploring genetic and immune underpinnings of the sexual dimorphism in tumor response to immune checkpoints inhibitors: A narrative review

“…In the last decade, immune checkpoint inhibitors (ICIs) have prompted a paradigm shift in the treatment of several solid and hematologic malignancies, including non-small cell lung cancer (NSCLC) ( Ribas and Wolchok, 2018 ), malignant melanoma and genitourinary cancers ( Lin et al., 2022 ; Lalani et al., 2022 ). At present, ICIs are approved for the first and more-line treatment in advanced NSCLC ( Pasello et al., 2020 ), with the notable exception of consolidation durvalumab, which is employed in unresectable locally-advanced NSCLC after radical chemoradiation (CRT) ( Gray et al., 2020 ).…”