Response to Immune Checkpoint Inhibitors Among Patients with NSCLC with RET Rearrangements

RET (rearrangement during transfection) is a tyrosine kinase receptor that, when fused with a partner molecule, activates oncogenic activity and promotes unchecked cellular proliferation.¹ RET rearrangements occur in 1% to 2% of cases of non–small-cell lung cancer (NSCLC).² It has been demonstrated that pemetrexed-based chemotherapy and multikinase inhibitors have modest effect for patients with RET-rearranged lung cancers,^2,3 and more targeted agents are in development but currently not available except through clinical trials and expanded access programs. Consequently, it is important to investigate the effects of immune checkpoint inhibitors in this patient population,⁴ which have been previously unknown.

Currently, 4 retrospective studies have described the effects of immune checkpoint inhibitors in patients with RET-rearranged lung cancer. In a retrospective study that included 551 patients, 16 patients had RET-rearranged NSCLC.⁵ The majority were diagnosed with adenocarcinoma and were treated with the PD-1 inhibitors nivolumab or pembrolizumab. Approximately 66.7% of patients with RET-rearranged NSCLC were never-smokers, 26.7% were former smokers, and 6.7% were current smokers. The median number of cells positive for PD-L1 expression was 26%. Patients were followed for a median of 16.1 months, and the objective response rate (ORR) among patients with RET rearrangements was 6%, and progressive disease was observed in 75% of patients. The median overall survival (OS) was 21.3 months (95% confidence interval [CI], 3.8-28.0), and median progression-free survival (PFS) was 2.1 months (95% CI, 1.3-4.7). The modest results suggest that immune checkpoint inhibitors should not be used as single agents in patients with RET-rearranged NSCLC.

A retrospective, multicenter study included 107 patients who were mostly treated with the PD-1 inhibitors nivolumab and pembrolizumab.⁶ Approximately 56% had PD-L1 expression ≥50%. The study specifically included 9 patients with NSCLC with RET rearrangements, of whom the majority had adenocarcinoma, and 44% were never-smokers, 33% former smokers, and 22% active smokers. Patients were followed for a median of 9.2 months. Patients with RET rearrangements had an ORR of 37.5%, the median duration of response was 12.1 months (95% CI, 8.4-not reached [NR]), median PFS was 7.6 months (95% CI, 2.3-NR), and median OS was not reached. It is important to note that the higher response rates in this study may be related to the fact that this patient population received immunotherapy as an earlier line of treatment than in other studies.⁶

Another study of 74 patients with RET-rearranged NSCLC included patients who were treated with the PD-1 inhibitors pembrolizumab, nivolumab, atezolizumab, durvalumab, or ipilimumab plus nivolumab.² Approximately 69% of patients were never-smokers and 31% were former smokers. PD-L1 expression ranged from 0% to ≥50% (58% of patients had 0% PD-L1 expression; 23% had 1%-49% PD-L1 expression; and 19% had ≥50% PD-L1 expression).² Among 13 patients assessed for response, progression of disease was observed in 62% of patients. The PFS was 3.4 months (95% CI, 2.1-5.6). One patient in this cohort highly expressed PD-L1 (50%), and despite this, responded poorly to dual immune checkpoint inhibitor therapy. These findings are consistent with previous studies showing that immune checkpoint inhibitors have little effect in patients with RET-rearranged NSCLC.

Finally, in a similar retrospective study of 59 patients with RET rearrangements in South Korea, approximately 51% of the total cohort were never-smokers, 28.8% were former smokers, 20.3% were current smokers, and the majority had adenocarcinoma.⁷ Among this cohort, 13 patients were treated with immune checkpoint inhibitors. The ORR in this patient population was 7.7%, the median PFS was 2.1 months (95% CI, 1.6-2.6), and the median OS was 12.4 months (95% CI, 2.9-21.8). Overall, patients in this study with RET rearrangements did not experience clinical benefit from immune checkpoint inhibitor treatment.

In summary, RET fusions affect 1% to 2% of patients with NSCLC, but these patients have not experienced substantial benefit from multikinase inhibitors. Although immune checkpoint inhibitors have become part of the standard of care for patients with NSCLC, studies now suggest they have inferior activity against RET fusions. The body of evidence indicates that tumors present among those with RET-rearranged NSCLC are biologically cold, suggesting that immune checkpoint inhibitors only be used after select targeted therapies.²

References

1. O’Leary C, Xu W, Pavlakis N, et al. Rearranged during transfection fusions in non–small-cell lung cancer. Cancers (Basel). 2019;11:620.
2. Offin M, Guo R, Wu S, et al. Immunophenotype and response to immunotherapy of RET-rearranged lung cancers. JCO Precis Oncol. 2019;3:10.1200/PO.18.00386.
3. Ackermann CJ, Stock G, Tay R, et al. Targeted therapy for RET-rearranged non–small-cell lung cancer: clinical development and future directions. Onco Targets Ther. 2019;12:7857-7864.
4. Baglivo S, Ludovini V, Moretti R, et al. RET rearrangement as a predictor of unresponsiveness to immunotherapy in non–small-cell lung cancer: report of two cases with review of the literature. Oncol Ther. 2020 May 20. Epub ahead of print.
5. Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30:1321-1328.
6. Guisier F, Dubos-Arvis C, Viñas F, et al. Efficacy and safety of anti-PD-1 immunotherapy in patients with advanced NSCLC with BRAF, HER2, or MET mutations or RET translocation: GFPC 01-2018. J Thorac Oncol. 2020;15:628-636.
7. Lee J, Ku BM, Shim JH, et al. Characteristics and outcomes of RET-rearranged Korean non–small-cell lung cancer patients in real-world practice. Jpn J Clin Oncol. 2020;50:594-601.