Several works have been published on the effectiveness of immunotherapy in patients with various rare molecular alterations. The analysed populations included patients with
RET fusion. Guisier et al. had determined immune checkpoint inhibitors (ICIs) effectiveness in NSCLC patients harbouring
BRAF,
HER2,
MET, and
RET genes abnormalities in a real-world setting. Among 107 patients, only nine had
RET translocation. Before ICIs, the patients had received one treatment line. For
RET-altered patients, mPFS was 7.6 months, median DOR was 4.7 months and the ORR—38% (3 patients—partial response, 2—stable disease, 3—progressive disease, and 1—not evaluable). However, the group of
RET-altered patients was too few in number to draw reliable conclusions about the effectiveness of ICIs in these patients [
19]. Offin et al. had reported ICIs effectiveness in 13 patients with
RET-rearranged lung cancer with low PD-L1 expression and low TMB. No response was achieved for patients receiving either single anti–PD-L1 or combination with anti-CTLA-4. Offin et al. had no representation of PD-L1-high tumours; therefore, the results are particularly related to a very small subgroup of patients [
15]. On the other hand, Hegde et al. showed that in patients with
RET-positive malignancies (medullary thyroid cancer, NSCLC and other types), time to progression was shorter when treated with ICIs compared to non-ICI therapy [
20]. The clinical effectiveness of therapy was related to the type of
RET pathway aberration: significantly higher risk of progression was observed for
RET-mutated (not translocated) malignancies treated with ICIs compared to non-ICI therapy [
20]. Lee et al. presented the clinical characteristics and the value of various methods of systemic treatment in a group of 59 patients with
RET fusion (most often KIF5B 21–65.6% and CCDC6 6–18.8%) [
21]. Selective RET inhibitors (pralsetinib/selpercatinib) were not used in this group treatment. The best outcomes were achieved using platinum-based and pemetrexed chemotherapy—mPFS of 9.0 months (95% CI: 6.9–11.2) and mOS of 24.1 months (95% CI: 15.2–33.0). Immunotherapy was used in 22% of the patients as first- or second-line treatment (nivolumab, pembrolizumab, atezolizumab), and in two patients combined treatment was administered as third-line treatment (durvalumab/tremelimumab). No objective response was observed in patients receiving PD-1/PD-L1 inhibitors, with disease control rate of 25-50%. Generally, mPFS was 2.1 months (95% CI: 1.6–2.6) and mOS—12.4 months (95% CI: 2.9–21.8) [
21] in all patients treated with immunotherapy whose cases were presented in the study. The high percentage of patients with brain metastases during follow-up should be noted; according to the study the metastases were observed in 60% of the patients in 24 months. Low intracranial activity of available treatment methods, including immunotherapy, poses a significant challenge in treatment of patients with
RET gene fusion. Bhandari et al. have recently published results of analysis using data from Flatiron Health-Foundation Medicine Clinico-Genomic Database and Guardant Health Database [
22]. In total, 264 patients with
RET fusion were identified and 69 of them had received immunotherapy as first- or second-line treatment. Median PFS in patients receiving immunotherapy as first-line treatment was 4.2 months (95%CI 1.4–8.4), while mOS—19.1 months (available data for 17 patients included in Clinico-Genomics Database) [
22]. For 12 patients who received chemoimmunotherapy as first-line treatment mPFS was 5.4 months and mOS—19.1 months (6.9-NR); ORR of 70% was noted. The authors confirmed the clinical profile of
RET positive NSCLC patients, which was mentioned above. The patients were younger, had fewer comorbidities, and lower smoking history than general population of NSCLC patients. TMB and PD-L1 expression data were also presented in the study. They were not complete, as they were available only for 10% of the patients, but PD-L1 expression <1% and TMB < 6 mutations per megabase were observed in most of the cases [
22].
The results of the above-mentioned retrospective studies and published case reports evaluating immunotherapy (monotherapy) in RET-rearranged patients are summarised in Table 1.
On the other hand, the place of RET inhibitors, with particular focus on the optimal sequence of treatment, is also an important issue. Most patients in the registration studies of selpercatinib and pralsetinib received drugs after the failure of previous therapies. Accordingly, registration records allow for the use of the drugs in previously treated patients. However, it should be noted, that some differences in ORR and mPFS were found depending on prior treatment status. For selpercatinib, ORR was 64% (95% CI: 54–73%) in pre-treated patients, while 85% in untreated patients (95% CI: 70–94%). The mPFS was, respectively, 17 months (95% CI: 14 months to unreached) and unreached [
14]. Among pre-treated patients, 55% had received anti-PD-1/PD-L1 antibodies. For pralsetinib, ORR was confirmed in 61% (95% CI 50–71%) of patients with previous platinum-based chemotherapy and in 70% (95% CI 50–86%) of treatment-naive patients [
13]. Among previously treated patients, all patients had received chemotherapy, and 45% had received immunotherapy. Responses were observed regardless of previous anti-PD-1/PD-L1 therapy status. The median of PFS in pre-treated group of patients was 17.1 months (95% CI 8.3–22.1). Overall survival data for selective
RET-inhibitors are still incomplete. Phase III studies comparing these drugs with chemotherapy or chemoimmunotherapy used in first-line treatment will provide more detailed data on survival parameters and safety profile. The safety of the treatment and possible interactions between TKIs and immunotherapy require special attention in the context of the sequential therapy.
Taking into account the data presented, which indicate questionable efficacy of immunotherapy and limited access to RET-inhibitors in the first-line treatment in patients with coexistent PD-L1 expression > 50% and RET-fusion, the use of chemotherapy based on platinum derivatives and pemetrexed may be considered.