Efficacy of first-line immune checkpoint inhibitors in pulmonary sarcomatoid carcinoma

Introduction

Pulmonary sarcomatoid carcinomas (PSC) are rare tumors, accounting for 0.4% of lung malignancies (1). PSC are associated with a shorter overall survival (OS) than conventional non-small cell lung cancer (NSCLC). Prior to the era of immunotherapy, metastatic PSC patients had a median OS ranging from 3.0 to 8.5 months (2-4). This poor prognosis can be attributed, at least in part, to the resistance of these tumors to standard chemotherapies (5). In 2020, our research group published a retrospective study involving 37 patients with PSC who received immunotherapy as a second-line treatment (6). The study reported an encouraging objective response rate (ORR) of 40.5%, a progression-free survival (PFS) of 4.9 months and an OS of 12.7 months. Based on these results, the primary objective of this retrospective study was to comprehensively assess the efficacy of immunotherapy, both as a monotherapy [immunotherapy alone (IO)] and in combination with chemotherapy (IO CT), as a first-line treatment of PSC. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-263/rc).

Methods

Patients and study design

All patients with histologically proven, stage III (ineligible for surgery or radio-chemotherapy) or stage IV PSC, and who received a first line of treatment with immunotherapy (either in combination with chemotherapy or other immunotherapy, or as monotherapy) between July 2017 and April 2021 were included in this analysis. Patients who had received chemotherapy as part of curative treatment (surgery or radio-chemotherapy) prior to the metastatic relapse were eligible. Patient data were searched in the archives of the Pneumology, Thoracic Oncology and Medical Oncology departments of 13 hospitals in the Ile-de-France region and collected retrospectively and anonymously from the medical records. The detailed histological reports with programmed cell death 1 ligand 1 (PD-L1) status at diagnosis were retrieved with a centralized reviewing (D.D.). Molecular biology reports were retrieved, with a centralized reviewing (K.L.). The routine panels used have limited sensitivity for detecting STK11 (covering only 30% of anomalies) and do not include KEAP1. Imaging reports at diagnosis and at each evaluation were analyzed [computed tomography (CT) and positron emission tomography-CT (PET-CT)] (G.B.).

Evaluation criteria

Radiological responses were defined in accordance with the Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1 (7). The ORR was defined as the proportion of patients achieving a partial or complete response according to RECIST. The disease control rate (DCR) was defined as the proportion of patients achieving stabilization, partial or complete response according to RECIST. PFS was defined as the interval between the start of a line of therapy to disease progression on that treatment. OS was defined as the time from initiation of treatment to death.

Data were updated 2 years after the last patient was included (April 2023).

Statistical analysis

The patients included were categorized according to their treatment modality into two groups: the IO CT group, comprising patients who received a combination of immunotherapy and chemotherapy, and the IO group, comprising patients who received either immunotherapy monotherapy or dual immunotherapy. Non-parametric tests (χ², Fisher and Mann-Whitney) were used to compare these two treatment groups. OS and PFS were estimated using the Kaplan-Meier method. Univariate and multivariate analyses of clinical data were performed to identify prognostic variables. All statistical analyses were conducted using GraphPad Prism version 10.0.3. Univariate analysis was performed with the use of an unpaired Student’s t-test or fisher’s exact test, as appropriate. Multivariate logistic-regression analysis was then performed, with backward stepwise analysis, to identify independent prognostic variables. All comparisons of clinical variables with a P value of less than 0.20 by univariate analysis were entered into the model. A P value of less than 0.05 was considered to indicate statistical significance.

Ethical considerations

The study protocol and the patient information note were reviewed and approved by the “Committee for the Evaluation of Observational Research Protocols” of the “French Respiratory Society (SPLF)” (No. CEPRO 2021-016). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). All participating hospitals/institutions were informed and agreed with this study. Patients under care at the investigational centers were informed of the option to withhold their medical data from being used for health research. None of the patients included in the study objected to the utilization of their medical records for research purposes. Patient data were anonymized at the point of collection and retained at Cochin Hospital, APHP, Paris.

Results

Patient characteristics

Thirteen centers agreed to participate in the study, with eight of them collectively enrolling a total of 34 patients (see Table 1). They were all non-irradiable stage III or stage IV. Among them, ten patients (29.4%) underwent surgery, and histological diagnosis was available for these patients on complete surgical specimens. For other patients, the diagnosis of PSC was made from small biopsies showing both an epithelial and sarcomatoid component. This diagnosis was supported using pan-cytokeratin (AE1/AE3, CAM5.2), epithelial membrane antigen (EMA), p40, and TTF-1 immunostaining (8). Most tumors (79.4%) were pleomorphic carcinomas. PD-L1 status was assessable for all patients, and all tumors exhibited positive PD-L1 expression (above the 1% threshold), with 31 tumors (91.2%) having a PD-L1 expression equal to or exceeding 50%. The clones used for PD-L1 status were QR1 (n=11), E1L3N (n=12), SP263 (n=1), and 22C3 (n=3) and not specified for seven patients. The mutational status of patients is summarized in Table S1. Next-generation sequencing analysis was available for 32 patients (94.1%). Among them, 20 patients (62.5%) carried at least one KRAS, MET, or BRAF oncogenic mutation. No patient was found to have an EGFR mutation, ALK or ROS1 fusion. No co-alterations of KEAP1 or STK11 were identified.

Patients were categorized according to treatment modality. In the IO CT group, patients received immunotherapy with pembrolizumab combined with either paclitaxel (n=4) or pemetrexed (n=7). In the IO group, patients received either pembrolizumab (n=21) or nivolumab-ipilimumab (n=2). The criteria for selecting between ICI monotherapy and ICI combined with chemotherapy were based on the prevailing guidelines at the time of patient treatment. The characteristics of the patients are summarized in Table 1.

The clinical characteristics were similar in the two groups, except for age (54.0 years in the IO CT group vs. 71.0 years in the IO group, P=0.02). Only three patients had PD-L1 expression below the 50% threshold, and all of them were in the IO CT group. Molecular characteristics were comparable in both groups.

Efficiency data—overall population

In the overall population, the ORR was 56% (n=19/34) and the DCR was 68% (n=23/34) (Figure S1). Three patients had a complete response (8.8%), 16 had a partial response (47.1%), 4 were stabilized (11.8%) and 11 had progressive disease (32.4%). The median duration of response was 20.5 months. The median PFS was 5.11 months, and the median OS was 13.9 months (Figure S1). First-line treatment was discontinued in 30 patients (88.2%), mainly due to progression (47.0%), death (17.6%), but also prolonged response exceeding 2 years (11.7%) and less frequently treatment-related toxicity (8.8%). Four patients were on active surveillance following a complete response and five patients were still receiving treatment at the last data update. Among the patients who discontinued first-line treatment, 15 (50%) received a second line. Out of the five patients with MET exon 14 skipping mutation, one received targeted therapy as second-line (crizotinib), two died during the first-line treatment, one exhibited a prolonged response for first- and second-line treatment (Table S2). None of the patients with KRAS G12C mutations received targeted therapy due to the study’s inclusion period, during which no therapy targeting KRAS was available.

Efficiency data—according to treatment

Efficacy parameters were subsequently evaluated based on the treatment administered.

As shown in Figure 1, there was a trend although not statistically significant for a better ORR (P=0.71) and DCR (P=0.06) in the IO CT group compared to the IO group. A similar trend was noted for PFS (P=0.12) and OS (P=0.33). The median PFS and OS for the IO CT group were 8.72 and 16.08 months, respectively, while those for the IO group were 3.45 and 13.11 months (Figure 1).

Figure 1 Immunotherapy efficacy according to treatment. (A) ORR, DCR and progression. (B) Kaplan-Meier plot for PFS. (C) Kaplan-Meier plot for OS. ORR, objective response rate; DCR, disease control rate; OS, overall survival; PFS, progression-free survival; CI, confidence interval.

Factor predictive of treatment efficacy

Univariate and multivariate analyses were carried out to identify prognostic factors in the study population. Univariate analysis on OS showed that performance status (PS) was the sole significant prognostic factor. We did not find any statistical difference PFS between stage III and stage IV patients. The multivariate analysis incorporated clinical variables with a P value of less than 0.20 from the univariate analysis. Inclusion of variables such as presence of cerebral metastasis, PS and high expression of PD-L1 (≥75%) showed that PS remained the sole predictive factor for a better OS (Figure 2). High PD-L1 did not exhibit a significant association with improved OS in both univariate and multivariate analyses in this patient cohort.

Figure 2 Prognostic factors in patients with pulmonary sarcomatoid carcinoma. (A) Univariate analysis on overall survival. (B) Multivariate analysis on overall survival. PD-L1, programmed cell death 1 ligand 1; PS, performance status; CI, confidence interval.

Discussion

In this cohort of 34 patients with metastatic PSC, first-line immunotherapy with or without chemotherapy was associated with an ORR of 56%, a PFS of 5.11 months and an OS of 13.9 months.

Phase III trials investigating immunotherapy with or without chemotherapy in non-sarcomatoid NSCLC have shown superior PFS and OS compared to our study (9-22) (Table S3). This discrepancy may be partially attributed to the poorer prognosis of PSCs and the more stringent eligibility criteria in phase III trials. Notably, these trials excluded patients with a PS greater than 1, whereas 17.6% of our study participants had a PS of 2. Nevertheless, when juxtaposed with historical data on PSC treatment before the immunotherapy era, where the ORR was below 20%, and OS ranged from 3.0 to 8.5 months, our findings underscore the benefits of immunotherapy for PSC (5,23).

Comparable findings have been reported by other teams in studies of PSCs treated with immunotherapy, either with or without chemotherapy (24-29) (Table S4). Across these studies, PFS ranged from 4.9 to 10.3 months, while OS ranged from 12.7 to 22.8 months. These studies are also retrospective, with sample sizes similar to our study. However, they differ in terms of treatment-line (first or subsequent), immunotherapy types (anti-PD-1, anti-PD-L1, anti-CTLA4), and whether combined with chemotherapy or anti-angiogenic agents, making direct comparisons challenging.

The choice among the two treatment options—immunotherapy with chemotherapy or immunotherapy alone—is particularly relevant for the management of PSCs, which are frequently associated with high PD-L1 expression on tumor cells (TC) (30): in our series, 91.2% of patients had PD-L1 TC expression greater than or equal to 50%. The limited response rate to conventional chemotherapies and the high PD-L1 TC expression of PSCs suggest that treatment with immunotherapy in monotherapy might be preferred in this situation. However, the frequent sarcopenia of PSC patients, the high tumor burden and the rapid progression of these cancers (2,5,31-33) could argue in favor of an approach combining immunotherapy and chemotherapy. By grouping patients based on their treatment, a trend emerged in favor of immunotherapy with chemotherapy over immunotherapy alone in terms of ORR, PFS, and OS.

Our study has several limitations, particularly a relatively small sample size and its retrospective nature. These aspects may raise questions about the comparability of patient characteristics between the two groups, notably regarding age. Although other variables such as PS did not exhibit a significant difference between the two groups, it is worth noting that 21.7% of patients in the IO group had a PS of 2, compared to 9.1% in the IO CT group, adding complexity to the interpretation of results.

The frequent occurrence of KRAS G12C mutations and MET exon 14 skipping in PSC patients emphasizes the need for a clearer understanding of the role of targeted therapies in managing these tumors (34). While studies have shown the effectiveness of immunotherapy for treating metastatic NSCLC with these mutations (35,36), caution is warranted due to increased toxicities observed in patients undergoing sequential immunotherapy followed by targeted therapy (37). In our cohort, 62.5% (n=20/32) had a driver mutation (Table S1), but only one received targeted therapy after immunotherapy, preventing a comprehensive assessment of toxicity in this context. In our cohort, the presence or absence of activating mutations (KRAS, BRAF, MET exon 14) did not predict immunotherapy efficacy. None of the patients had an EGFR mutation or ALK translocation, typically associated with a poorer prognosis under immunotherapy (38,39).

Conclusions

Our retrospective study of advanced or metastatic PSC patients treated with IO alone or in combination with chemotherapy demonstrated an improvement in clinical outcomes with a trend toward prolonged PFS and OS in patients treated with the combination of IO and chemotherapy. Prospective studies are needed to determine the optimal treatment modality for these patients.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-263/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-263/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-263/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-263/coif). N.G. received research grants/support from Abbvie, Amgen, AstraZeneca, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Gilead, Hoffmann-La Roche, Janssen, LeoPharma, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Sanofi, Sivan; provided consultative services for Abbvie, Amgen, AstraZeneca, Beigene, Bristol Myers Squibb, Daiichi-Sankyo, Gilead, Ipsen, Hoffmann-La Roche, Janssen, LeoPharma, Lilly, Merck Sharp & Dohme, Mirati, Novartis, Pfizer, Pierre Fabre, Sanofi, Takeda; participated on a data safety monitoring board for Hoffmann-La Roche; employment of a family member with AstraZeneca. Jacques Cadranel received consulting fees for participation to boards of experts from AMGEN, AZ, Daiichi (and travelling, BMS, MSD, Roche, Sanofi, Janssen (and travelling), Takeda, Pfizer (and travelling). I.M. received honoraria from Regeneron and support from Takeda, MSD, Pfizer, Oxyvie. E.G.L. received honoraria from AMGEN, AstraZeneca, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, Takeda and support for attending meetings and/or travel from Takeda, MSD, AstraZeneca. K.L. received honoraria from AstraZeneca, MSD, Janssen, GSK, Lilly, AMGEN, Roche for lectures, presentations or educational events and support for attending meetings and/or travel from AMGEN. Jeanne Chapron received honoraria from BMS, AstraZeneca, Pfizer, Sanofi, MSD and support for attending meetings and/or travel from Sanofi and Regeneron. M.W. received payment or honoraria for lectures and presentations from AMGEN, AstraZeneca, Bristol Myers Squibb, F. Hoffmann-La Roche, Janssen, MSD Oncology, Lilly, Merck KGaA; grants from AstraZeneca; support for attending meetings and/or travel from Janssen, Amgen, MSD and F. Hoffmann-La Roche; participated on a data safety monitoring board or advisory board for AMGEN, AstraZeneca, Bristol Myers Squibb, F. Hoffmann-La Roche, Janssen, MSD Oncology, Lilly and Merck KGaA. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study protocol and the patient information note were reviewed and approved by the “Committee for the Evaluation of Observational Research Protocols” of the “French Respiratory Society (SPLF)” (No. CEPRO 2021-016). All participating hospitals/institutions were informed and agreed with this study. Patients under care at the investigational centers were informed of the option to withhold their medical data from being used for health research. None of the patients included in the study objected to the utilization of their medical records for research purposes.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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