Long-Term Complete Response to Pembrolizumab in Tumor Mutation Burden-High Small Cell Lung Cancer: A Case Report

Abstract

Introduction

Extensive-stage small-cell lung cancer (ED-SCLC) has a poor prognosis. There are few case reports on the therapeutic effect of pembrolizumab in advanced SCLC with high tumor mutation burden (TMB-high).

Case Presentation

A 65-year-old woman was diagnosed with ED-SCLC. The initial treatment regimen included carboplatin, etoposide, and durvalumab. Following the administration of durvalumab, etoposide was discontinued due to an anaphylactic reaction immediately after its initiation. The patient was unable to continue the same regimen and was switched to cisplatin and irinotecan therapy. A FoundationOne panel test was submitted at the same time, and TMB-high was detected. After four courses of cisplatin and irinotecan therapy, pembrolizumab was introduced, and a complete response (CR) was maintained for 18 months.

Conclusion

We report a rare case of a long-term response to pembrolizumab in ED-SCLC with TMB-high, highlighting the potential for targeted immunotherapy in such cases.

Introduction

Small-cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor that accounts for approximately 15% of all lung cancers [1]. Despite initial sensitivity to chemotherapy and radiotherapy, many patients experience relapse within a year, leading to a poor prognosis. In recent years, immune checkpoint inhibitors (ICIs) combined with platinum-based chemotherapy have shown positive results in treating extensive-stage SCLC (ED-SCLC) [2]. However, while these treatments have statistically significant outcomes, their effect on overall survival (OS) is limited, prolonging it by only 2.2–2.4 months [3, 4]. Identifying biomarkers of ICI response is a pressing issue as some cases show improved long-term prognosis, although PD-L1 expression in tumor cells and tumor mutation burden (TMB) in tumor tissue are established predictors of ICI efficacy [5].

Based on the results of the KEYNOTE-158 and KEYNOTE-028 trials [6, 7], which involved patients who had received two or more lines of previous therapy to explore the efficacy and safety of pembrolizumab monotherapy, pembrolizumab was approved in the USA in June 2019 for treating TMB-high ED-SCLC with a history of platinum-based chemotherapy [8]. In a report presenting the integrated analysis of these trials, the median progression-free survival (PFS) for pembrolizumab in ED-SCLC with two or more prior lines of therapy was only 2 months, and the median overall survival (OS) was 7.7 months [8]. Herein, we report a rare case of ED-SCLC that achieved long-term remission lasting over 18 months with pembrolizumab treatment.

Case Presentation

A 65-year-old woman with a history of palmoplantar pustulosis was referred to our hospital for the evaluation of a breast mass and a chest mass (Fig. 1a, b). Histopathological analysis of biopsy specimens from both the lung mass and the breast mass revealed small cell carcinoma in both lesions (Fig. 1c–f). The breast mass was determined to be a metastatic lesion from primary SCLC. Comprehensive staging, including contrast-enhanced MRI of the brain and FDG-PET, led to a diagnosis of stage cT2aN3M1c.

Fig. 1.

a PET-CT scan findings showed not only the primary lesion in the right upper lobe and the right breast, but also multiple bone metastases, peritoneal metastases, and skin metastases. b An enhanced chest CT examination revealed a primary lesion in the right upper lobe, as well as a heterogeneous mass in the right breast. Pathological analysis of CT-guided biopsy of a thoracic mass is shown. c Hematoxylin and eosin (HE) staining. The staining revealed diffuse proliferation of small tumor cells with a high nuclear-to-cytoplasmic (N/C) ratio. d Synaptophysin staining; negative. e Chromogranin staining; negative. f INSM1 staining; positive.

As first-line treatment, combination therapy of carboplatin (CBDCA), etoposide (ETP), and durvalumab was initiated. The administration sequence was durvalumab, followed by ETP, and then CBDCA. During the first course of treatment, the patient experienced anaphylactic shock while receiving an ETP infusion on day 1. The administration of ETP was immediately discontinued, and cimetidine, dexamethasone, and chlorpheniramine were administered, along with a saline infusion. Following the administration of these medications, the patient’s symptoms improved, and there was no recurrence of the anaphylactic reaction.

Given the difficulty in continuing the same regimen, the treatment was switched to combination therapy with cisplatin (CDDP) and irinotecan (CPT-11). After four courses of this treatment, significant reductions in both the lung and breast masses were observed (Fig. 2a, b). Analysis of the tumor tissue using the FoundationOne panel revealed a TMB of 10 mutations per megabase (Mb), making the use of pembrolizumab feasible. Additionally, the microsatellite status was stable, and TP53 V172F, PTEN L128N, RB1 loss, SOX2, PIK3CA, and FGF12 amplifications were detected. Pembrolizumab monotherapy successfully suppressed tumor progression and maintained a complete response for over 18 months (Fig. 2c). The treatment course of this patient is shown in Figure 3. One week after initiating Pembrolizumab treatment, the patient developed papules and pustules on both palms and soles. This was diagnosed as an exacerbation of the patient’s pre-existing palmoplantar pustulosis. Treatment with topical steroids was initiated, and the symptoms have been well controlled.

Fig. 2.

Table of follow-up CT scan results for evaluating treatment effectiveness. The upper row is an image of mediastinal conditions from a contrast-enhanced CT scan, and the lower row is an image of lung field striations. a CT image before treatment. b Four months after the initiation of chemotherapy, the primary lesion and breast mass showed a partial response. c Eighteen months after the initiation of pembrolizumab, the primary lesion and breast mass demonstrated a complete response. Red arrows indicate a primary lung lesion and blue arrows indicate a breast metastasis.

Fig. 3.

Time line of treatment for the present patient. CBDCA, carboplatin; ETP, etoposide; CDDP, cisplatin; CPT-11, irinotecan; ED, extended disease; SCLC, small-cell lung cancer; CGP, comprehensive genome profiling; TMB, tumor mutation burden.

Discussion

In this case, we report an instance where an anaphylactic reaction to ETP prevented the continuation of first-line treatment with a combination of CBDCA, ETP, and durvalumab. However, comprehensive genomic profiling (CGP) detected TMB-high, allowing the patient to receive pembrolizumab and achieve a long-term response. Anti-PD-1/PD-L1 antibodies are associated with improved long-term prognosis in SCLC, emphasizing the importance of linking these cases to immunotherapy.

The CASPIAN study showed that the combination of platinum-based chemotherapy, ETP, and durvalumab significantly improved survival compared to conventional chemotherapy (median survival: 13.0 months vs. 10.3 months, HR 0.73, p = 0.0047) [9]. If there had been no allergic reaction, I would have continued with CDDP+ETP+durvalumab based on this strong evidence.

Both durvalumab and pembrolizumab target the PD-1/PD-L1 pathway, but the marked response to pembrolizumab in this case may also be related to the TMB-high status. As TMB status was not assessed in the CASPIAN study [9], it is difficult to determine whether a similar complete response would have been achieved with durvalumab.

Pembrolizumab is approved for use across various cancer types when TMB-high (≥10 mut/Mb) is detected by CGP panel testing in advanced solid tumors expected to complete standard therapy [10]. TMB-high is thought to produce many tumor-specific antigens that induce immune responses [11]. Recently, TMB-high has attracted attention as a biomarker predicting the therapeutic effect of immune checkpoint inhibitors.

In the pooled analysis of the KEYNOTE-028 and -158 trials [6, 7], pembrolizumab showed efficacy against extensive-stage SCLC with TMB-high that had no history of immunotherapy and was expected to complete standard therapy. Although the median PFS of pembrolizumab was only 2 months, 13.1% of patients were able to continue treatment for 24 months or more. In the KEYNOTE-158 trial, 34 out of 76 patients (44.7%) with advanced or recurrent SCLC who had prior chemotherapy were identified as TMB-high (≥10 mutations/megabase [mut/Mb]) [8]. The choice to start pembrolizumab immediately after a favorable response to CDDP+CPT-11 is based on several considerations. First, recent evidence suggests that baseline tumor size is an important predictor of immunotherapy efficacy [12]. Second, the detection of a TMB-high status potentially indicated a high response to Pembrolizumab [8]. From these perspectives, we chose to introduce Pembrolizumab at this optimal timing when the tumor volume had decreased. In this case, we aimed to reduce the tumor volume as much as possible using a combination of CDDP and CPT-11, followed by the induction of immunotherapy. If TMB-high had not been detected by CGP testing, immunotherapy could not have been introduced.

Also, there are a certain number of patients who achieve a CR with only a cytotoxic agent. However, in the reference arm of the CASPIAN study, there was no population that maintained PFS for 18 months or more with a cytotoxic agent [9]. Therefore, in the case of ED-SCLC, it is difficult to say that the anti-tumor effect of a cytotoxic agent is permanent, and we think that the anti-tumor effect and long-term response are related to immune checkpoint inhibitors.

In SCLC, CGP testing rarely identifies targetable driver alterations, limiting the efficacy of targeted therapies [13]. Although the significance of using CGP testing in SCLC patients is unclear, it may be useful for patients who, for some reason, cannot receive immunotherapy as first-line treatment, as demonstrated in this case.

The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000544103).

Statement of Ethics

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors declare the following financial interests/personal relationships which may be considered potential competing interests: Dr. Kei Kunimasa reports honoraria for lecture from AstraZeneca, Chugai Pharma, and Novartis; Dr. Motohiro Tamiya reports receiving grants from Boehringer Ingelheim, Ono, MSD, Eisai, Daiichi Sankyo, Chugai, and Janssen and personal fees from Boehringer Ingelheim, Ono, MSD, Chugai, AstraZeneca, Taiho, Eli Lilly, Novartis, Asahi Kasei, Bristol Myers Squibb, Bayer, Amgen, Kyowa-Kirin, and Nippon Kayaku. Dr. Kazumi Nishino reports receiving grants from Ono, TAIHO, MSD, AbbVie, DAIICHI SANKYO, Amgen, Eisai, Sanofi, Janssen, Novartis, Pfizer, Eli Lilly, Merck, Takeda, Chugai, and Merus and personal fees from AstraZeneca, Chugai, Nippon Boehringer Ingelheim, Eli Lilly, Roche, Novartis, Pfizer, Merck, Janssen, Bristol Myers Squibb, and Nippon Kayaku. The remaining authors declare no conflict of interest.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Kiyohide Komuta: conceptualization, investigation, methodology, and writing – original draft. Kei Kunimasa: conceptualization, investigation, methodology, writing – original draft, and writing – review and editing. Akito Miyazaki, Shun Futamura, Tsunehiro Tanaka, Takahisa Kawamura, Takako Inoue, and Motohiro Tamiya: investigation and writing – review and editing. Kazumi Nishino: conceptualization, investigation, supervision, and writing – review and editing.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

The data that support the findings of this study are not publicly available because they contain information that could compromise the right to privacy and confidentiality of the participants. However, these data are available from the corresponding author (Kei Kunimasa, kei.kunimasa@oici.jp) upon reasonable request.