Third\line cytotoxic chemotherapy has been reported to have a low response rate of 3C9%.6, 7 Recently, three retrospective studies, including a caseCcontrol study, presented a promising response rate of 25C39% after salvage chemotherapy following exposure to PD\1/PD\L1 inhibitors (Table 1).1, 2, 3 The caseCcontrol study revealed an odds ratio of 0.30 (95% confidence interval 0.18C0.50) for achieving a partial response to salvage chemotherapy.1 In phase I/II trials, concurrent administration of the PD\1 inhibitor with first\line chemotherapy showed a high response rate of 50%.8, 9 Chemotherapy has been suggested to synergize with PD\1 inhibitors in some lung cancer patients. Table 1 Treatment Nog outcomes of salvage chemotherapy following exposure to immune checkpoint inhibitors, as reported in the literature thead valign=”bottom” th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ Study design /th th align=”center” valign=”bottom” rowspan=”1″ colspan=”1″ Number of patients /th th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ Number of lines of prior chemotherapy /th th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ Immune checkpoint inhibitors /th th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ Salvage chemotherapy /th th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ Efficacy of salvage chemotherapy /th th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ Reference /th /thead Retrospective caseCcontrol study67Mean: 2.4 (95% CI 2.1C2.6)Nivolumab (84%)DTX (62%)ORR: 27%Leger em et al /em .1 Pembrolizumab (10%)PEM (20%)Odds ratio: 0.30 (95%CI: 0.18C0.50)Atezolizumab (6%)GEM (12%)PTX (6%)Retrospective cohort study28Median: 2 (range 1C4)Nivolumab (86%)DTX (50%)ORR: 39%Schvartsman em et al /em .2 Pemrolizumab (10%)GEM (21%)Durvalumab (4%)PEM (11%)MMC (11%)Other (7%)Retrospective cohort study32Median: 2 (range 1C6)NivolumabPTX?+?RAM (38%)ORR: 25%Grigg em et al /em .3 PembrolizumabVNR (22%)AtezolizumabGEM\based (19%)DurvalumabCBDCA doublets (13%)Others (8%)Case study22NivolumabS ? 1PRPresent study3NivolumabCBDCA/nab PTXPR Open in a separate window CI, confidence interval; CBDCA, carboplatin; DTX, docetaxel; GEM, gemcitabine; MMC, mitomycin C; nab\PTX, albumin\bound PTX; ORR, overall response rate; PEM, pemetrexed; PR, partial response; PTX, paclitaxel; RAM, ramucirumab; VNR, vinorelbine. In one of two cases, the pretreatment lung cancer cells highly expressed PD\L1 and were accompanied by predominantly infiltrating CD8+ lymphocytes; regulatory T LPA2 antagonist 1 cells and TIM\3+ cells were also included. further enlarged after a total of six?cycles of nivolumab, the possibility of pseudoprogression was considered and treatment was continued. Open in a separate window Figure 1 Chest computed tomography scans of a patient with undifferentiated non\small cell lung cancer. (a) Before treatment with nivolumab, a 28?mm tumor is seen in the left lower lobe of the lung. (b) After nine courses of nivolumab therapy, the diameter of the lung tumor increased to 55?mm. (c) After treatment with two courses of S?1, the lung tumor decreased to 20?mm in diameter. Despite nine?cycles of nivolumab, disease progression and an increasing cough were evident (Fig ?(Fig1b).1b). Three weeks after the last administration of nivolumab, the treatment regimen was changed to S?1 at a dose of 60?mg twice daily for 28 consecutive days, followed by a two\week rest period. S?1 has been reported to show efficacy and safety in previously treated NSCLC patients. 4 The tumor rapidly regressed, resulting in a partial response six weeks later (Fig ?(Fig1c).1c). The patients lung cancer has remained progression\free for five?months. Histopathologic review of the transbronchial biopsy specimen at the time of diagnosis showed large, undifferentiated cancer cells (Fig ?(Fig2a).2a). Immunohistochemical examination indicated that 90% of the tumor cells expressed PD\ligand 1 (PD\L1) (Fig ?(Fig2b).2b). CD3+ T\lymphocytes were found in the tumor stroma (Fig ?(Fig3a).3a). Infiltration of CD8+ cells was more predominant than CD4+ cells (Fig ?(Fig3b,c).3b,c). FOXP3+ regulatory T\cells and cells positive for TIM\3+ were included in the tumor stroma (Fig ?(Fig33d,e). Open in a separate window Figure 2 Photomicrographs of a transbronchial biopsy specimen of a patient with undifferentiated non\small cell lung cancer. (a) Large, undifferentiated cancer cells are seen in the fibrous tissue (hematoxylin & eosin stain, original magnification 400). (b) Immunohistochemical examination shows that 90% of the tumor cells expressed programmed death ligand\1 at a high intensity (original magnification 400). Open in a separate window Figure 3 Immunohistochemical profiles of the tumor\infiltrating lymphocytes in a patient with undifferentiated non\small cell lung cancer. (a) CD3+ lymphocytes, (b) CD8+ cells, (c) CD4+ cells, (d) FOXP3+ regulatory T\cells, and (e) TIM\3+ cells are seen in the tumor stroma (original magnification 100). The antibody clones used are as follows: CD3 (F7.2.38), CD8 (4B11), CD4 (4B12), FOXP3 (236A/E7), and TIM\3 (D5D5R). Case 2 A 75\year\old male former smoker was diagnosed with stage IIIA lung adenocarcinoma with pulmonary metastases. No mutation or rearrangement was detected. The patient underwent treatment with cisplatin/pemetrexed, followed by docetaxel and S?1. LPA2 antagonist 1 The best response after each regimen was a partial response, stable disease, and progressive disease, respectively. Eighteen months after the initiation of chemotherapy, the lung tumor enlarged (Fig ?(Fig4a)4a) and the serum CYFRA 21\1 level increased from 2.9?ng/mL to 4.5?ng/mL (reference value 3.5?ng/mL). Open in a separate window Figure 4 Chest computed tomography scans of a patient with lung adenocarcinoma. Before treatment with nivolumab, (a) a 45?mm primary tumor is observed in the left lower lobe of the lung. (b) After six courses of nivolumab therapy, the primary lung tumor increased to 75?mm in diameter. (c) After two courses of carboplatin/albumin\bound paclitaxel therapy, the primary lung tumor decreased to a diameter of 25?mm. The patient was administered nivolumab as fourth\line therapy; however, after three?cycles, the tumor increased in size. After six?cycles of nivolumab, disease progression was evident (Fig ?(Fig4b)4b) and the CYFRA 21\1 level further increased to 6.4?mg/mL. Three weeks after the last administration of nivolumab, his therapy was changed to carboplatin/ albumin\bound paclitaxel, which was administered to target an area under the blood concentration\time curve of 5?mg/mL/min on day 1, and a dose of 100?mg/m2 on days 1, 8, and 15. Carboplatin/albumin\bound paclitaxel has been reported to show promising efficacy and tolerability in previously treated patients with NSCLC.5 One month later, the tumor rapidly regressed, leading to a decrease in the CYFRA 21\1 level to LPA2 antagonist 1 2.3?ng/mL. Two months later, a partial response was achieved (Fig ?(Fig4c).4c). The patients lung cancer has remained progression\free for five?months. The remaining transbronchial biopsy specimen taken for diagnosis was insufficient for retrospective evaluation of PD\L1 expression. Written informed consent for the publication of these case reports was obtained from the patients. Conversation In this case study,.