Remarkable response to pembrolizumab with platinum‐doublet in PD‐L1‐low pulmonary sarcomatoid carcinoma: A case report

Abstract Pulmonary sarcomatoid carcinoma (SC) is an aggressive subtype of lung cancer that exhibits resistance to cytotoxic chemotherapy. Although programmed cell death 1 (PD‐1) inhibitors have been reported to show antitumor effects in patients with high programmed death‐ligand 1 (PD‐L1) expressing SC, the efficacy of combined therapy with PD‐1 inhibitor plus cytotoxic chemotherapy has not previously been clarified. We herein report a case of SC with low expression of PD‐L1 and few pre‐existing tumor‐infiltrating lymphocytes which showed a remarkable response to pembrolizumab plus cytotoxic chemotherapy as first‐line treatment. Our findings suggest that combined treatment might enhance the immunogenic response, even in immunologically ignored SCs.


INTRODUCTION
Pulmonary sarcomatoid carcinoma (SC) is a rare type of non-small cell lung cancer (NSCLC) with a poor prognosis due to rapid tumor growth, early metastasis, and resistance to platinum-based standard chemotherapy. 1,2 Novel therapeutic strategies for the treatment of SC are urgently needed to improve clinical outcomes.
Immune checkpoint inhibitors (ICIs) that block programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1), either as single agents or in combination, have led to revolutionary treatments for NSCLC. [3][4][5][6][7] A recent retrospective study suggested that single use of PD-1 inhibitor was effective in SC patients as a second-or third-line treatment. 8 However, the efficacy of PD-1 inhibitor with platinum-doublet, especially as first-line treatment, has not yet been elucidated.
Here, we report a patient with SC who showed a remarkable tumor response to PD-1 inhibitor, pembrolizumab with carboplatin (CBDCA) plus pemetrexed (PEM), regardless of PD-L1 tumor proportion score (TPS) 1%, and few tumorinfiltrating lymphocytes (TILs) and few PD-1 + immune cells were observed in tumor biopsy samples.

CASE REPORT
A 65-year-old male patient presented to our hospital with a history of a cough and hip joint pain.  However, treatment was discontinued because the patient developed pneumonitis and colitis which were considered to be severe immune-related adverse events (iRAEs) (Figure 3(a)-(c)). The patient commenced immunosuppressive treatment with 60 mg of prednisolone 38 days after the initiation of the fourth cycle of treatment. His pneumonitis and colitis fortunately improved; however, the tumor in his left lung had a significant regrowth 84 days after the initiation of prednisolone (Figure 2(c)), whereas the site of bone metastasis was stable, probably due to prior irradiation. After the iRAEs had subsided, the patient received docetaxel (60 mg/m 2 ) plus ramucirumab (10 mg/kg) as second-line treatment because the tumor size had evidently increased in size at that point. However, the mass in the left lung significantly increased after two cycles of docetaxel plus ramucirumab treatment (an increase in diameter from 93 mm before treatment to 125 mm after treatment). The patient chose not to receive third-line therapy and continued with best supportive care due to a decrease in performance status. Written informed consent for the publication of this case report was obtained from the patient. This case study was approved by the Institution Review Board of the ethics committee of our institution (Approval #20122147).

DISCUSSION
PD-1 inhibitors have demonstrated novel therapeutic success by overcoming tumor-induced T cell inhibition. CD8 + positive T cells are considered a critical component of antitumor immune response, and increased levels of CD8 + TILs have previously been reported to be associated with better outcomes in 552 patients with NSCLC. 9 Pre-existing CD8 + T cells distinctly located at the invasive tumor margin have been demonstrated to predict the response to ICIs in several types of cancers. 10,11 Expression of PD-L1 on tumor cells has also been shown to be a predictive factor for the efficacy of PD-1 inhibition in many solid tumors, including NSCLC. 6,12 Inflammatory cytokines such as IFNγ upregulate PD-L1 expression in various cell types and TILs release IFNγ as an adaptive immune resistance. 13 Thus, TILs or expression of PD-L1 on tumors have been reported as predictive markers for the effectivity of PD-1 inhibitors. A previous study reported that the response rate of PD-1 inhibitors tended to be lower in the lower PD-L1 expression cases in SCs. 8 On the other hand, recent clinical trials showed that the addition of PD-1 or PD-L1 inhibitor with platinum-doublet resulted in significantly longer overall and progression-free survival (PFS) than placebo with platinum-doublet across all categories of PD-L1 expression in patients with NSCLC. 4,5 In addition to direct antitumor effects, a combination of PD-1 inhibitor with cytotoxic chemotherapy has previously been reported to enhance the immunogenic response by the release of potentially immunogenic tumor antigens, promotion of the infiltration of CD8 + T cells, and increasing the ratio of cytotoxic lymphocytes to regulatory T cells, [14][15][16] even in patients with NSCLC that lacked pre-existing T cell infiltrates or low PD-L1 expression, as in the present case.
There are some limitations in the case reported here. The samples that were evaluated might not have captured the whole tumor microenvironment completely because they were obtained by needle biopsy, although the same results were obtained from two other tumor sites. Another limitation is that the tumor shrinkage might partially have been due to the abscopal effect wherein local irradiation can reduce the size of the nonirradiated site mediated by the immune system. 17 In conclusion, pembrolizumab with CBDCA plus PEM demonstrated antitumor activity in SC with low PD-L1 expression and few TILs. Further studies using a large cohort are needed to elucidate whether this therapeutic approach contribute to the survival of patients with SC across all categories of PD-L1 expression and pre-existing TILs.

ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing.