Patient characteristics and treatment outcome
Of the 114 patients who were previously treated for advanced NSCLC and who received nivolumab therapy, 7 patients were excluded from the study because they did not have RECIST-defined measurable lesions or they were not adequately evaluated for tumor response (Figure 1). Finally, 107 patients were included in the study; the patients’ characteristics are summarized in Table 1. The mean age of included patients was 68.2 years, and most patients were men (72%), had a history of smoking (75%), Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 (93%), and adenocarcinoma histology (74%). The total objective response by RECIST criteria was 22%; 19% of the patients had SD, and 59% had PD. At the time of analysis, 47 OS events (44%) had occurred. The median OS and estimated 1-year OS rate were 16.3 months and 42%, respectively.
Characteristics and treatment course of cases with DR
DR was observed in 5 patients (5%). The comparison between DR and non-DR patients revealed no significant differences in the patients’ characteristics (Table 1). Treatment course and a representative CT scan of patients with DR are shown in Figure 2.
Patient No. 6 was a 68-year-old man with advanced lung adenocarcinoma (Figure 2A). He started nivolumab as a second-line therapy. After the four cycles of nivolumab treatment, his primary lesion reduced in size (33 mm to 22 mm), although a new metastatic lesion (10 mm) in his brain was detected on the MRI scan; therefore, DR was diagnosed. His RECIST-defined tumor assessment was PD due to the new lesion and unconfirmed progressive disease (iUPD) by the iRECIST criteria. Nivolumab treatment was continued; thereafter, his tumor remained stable (iUPD by the iRECIST criteria). After 21 cycles of nivolumab, he developed immune-related diarrhea, and nivolumab was permanently interrupted. His tumors remained stable. After 729 days of nivolumab treatment, he experienced iPD by the iRECIST criteria (PD in primary lesion and brain metastasis).
Patient No. 28 was a 53-year-old woman with advanced lung adenocarcinoma. She began nivolumab as a third-line therapy (Figure 2B). After 5 cycles of nivolumab, her primary lesion reduced in size; however, her axial lymph node was enlarged (minimal diameter was 15 mm), and DR was diagnosed. Her RECIST-defined tumor response was PD, and her iRECIST-defined tumor assessment was iUPD. Nivolumab treatment was continued for another 6 cycles, until treatment was discontinued because of the onset of immune-related diarrhea. Her tumor remained stable (iUPD by iRECIST criteria). After 234 days of nivolumab treatment, the tumors were radiologically stable, but her serum levels of carcinoembryonic antigen (CEA) and cytokeratin-19-fragment (CYFRA) were elevated. Her attending physician diagnosed the condition as clinical PD, and she started fourth-line chemotherapy.
Patient No. 40 was an 80-year-old man with advanced lung adenocarcinoma (Figure 2C), and he was given nivolumab as a third-line therapy. After 3 cycles of nivolumab, his primary lesion was enlarged and pleural effusion was increased, although his pleural dissemination was reduced; thus, DR was diagnosed. His overall tumor assessment by RECIST was SD and that by iRECIST was iSD, and nivolumab treatment was continued. After 3 additional cycles of nivolumab, his primary lesion enlarged and was diagnosed as RECIST-defined PD.
A summary of the patients’ clinical courses is shown in Figure 3 and Supplementary Table 1. At DR diagnosis, 2 patients showed RECIST-defined PD and 3 patients showed RECIST-defined SD. The PD-L1 TPSs for these patients were 10% (No. 6), 30% (No. 28), 0% (No. 40), unknown because of low amount of specimen (No. 62), and 1% (No. 65). The times to treatment failure from commencement of nivolumab were 729, 234, 100, 174, and 151 days, respectively. Of the 5 patients, 2 achieved a durable clinical benefit. In this cohort, all patients continued nivolumab after DR, and local therapy was not conducted for the progressive lesion.
Pathological analysis of the DR site
Of the 5 patients with DR, 2 consented to tumor biopsies of the growing lesion (No. 40 and No. 65). In Patient No. 40, adenocarcinoma was diagnosed in the cell block analysis of the pleural effusion (Supplementary Figure 1A), which showed the same histology as the primary lesion (Supplementary Figure 1B). There was no evidence of other etiologies of pleural effusion, such as infection. Patient No. 65 underwent kidney biopsy, which revealed adenocarcinoma (Supplementary Figure 1C). Interestingly, this patient had an adenosquamous histology in the primary lesion (Supplementary Figure 1D); thus, a histological temporal heterogeneity was found between the primary and metastatic lesion.
Response patterns and OS
Patients showing DR had significantly longer OS than those showing concordant PD (PD without DR) (not reached vs. 8.0 months, respectively; p = 0.039). In addition, there was no significant difference in the OS between patients who showed concordant PR (PR without DR) and those who showed concordant SD (SD without DR) (not reached and not reached, respectively; p = 0.19 and p = 0.79, respectively). The data and Kaplan-Meier curves for OS are shown in Figure 4 and Supplementary table 2.
Comparison between ICI, chemotherapy, and TKI treatment
There were 150 patients in the chemotherapy group and 92 patients in the TKI group, and the frequencies of DR were 1% (2/150) and 4% (4/92), respectively (Figure 5). Increased frequencies of DR were observed in the ICI and TKI groups compared with that in the chemotherapy group; however, the differences were not statistically significant. None of the patients in the chemotherapy and TKI cohorts achieved durable clinical benefit.