Background
The dawn of the targeted therapy era saw the discovery of receptor tyrosine kinase
RET fusion in 1–2% of non-small cell lung cancers (NSCLC) [
1,
2] and proved it to be tumorigenic and targetable. Regarding the tumorigenicity, although several studies reported the prevalence of concomitant genetic alterations based on a limited sample size [
3‐
6], the effects of these concomitant alterations on clinical outcomes were scant.
Regarding the druggability, since more specific and potent TKIs targeting
RET such as BLU-667 and LOXO-29 2[
7‐
9] are currently not available for all of the patients, the common systemic treatment regimen now includes multikinase inhibitors (MKIs), chemotherapy, and immune checkpoint inhibitors (ICIs). The success of traditional MKIs is relatively limited [
10‐
14]. The median progression-free survival (PFS) of the pemetrexed/platinum regimen was 19 months, 7.5 months, and 6.4 months in a single center [
15], a Chinese cohort [
5], and an international cohort [
10], respectively. Although ICIs have been widely accepted, the outcomes of these treatment strategies in
RET-altered patients have not currently been well compared, and the immuno-characteristics in those patients have also not been well characterized in previous studies [
16,
17].
Here, we describe genetic and immune profiling in a multicenter cohort of patients with RET-rearranged NSCLC, analyze their associations with clinical outcomes, and document treatment outcomes in routine clinical care.
Discussion
Despite the rarity of this driver gene, we report a relatively large sample of multicenter patients with RET-altered NSCLC with therapies commonly used in clinical practice. We demonstrate that this group of lung cancers is characterized by heterogeneous genotype and PD-L1 expression, as well as low TMB. Patients harboring concomitant TP53 were associated with inferior overall survival. We also found prognostic significance of TCR repertoire diversity in the peripheral blood. Although a subgroup of patients could benefit from ICIs, the optimal treatment option in routine clinical care remains to be defined.
In this study, we found an unfavorable clinical outcome in
RET/TP53 co-mutated patients. Compared with other genes,
TP53 co-mutations occur rather frequently with
RET fusions. Recent works have suggested a negative impact of
TP53 mutations on the outcomes of patients with
EGFR-mutant [
33,
34] and
ALK-rearranged NSCLC [
35,
36]. However, in
RET-positive lung cancers, concomitant
TP53 mutations have not been described as poor prognostic factors. The negative prognostic effect of
TP53 mutations might be attributed to their tumor-suppressive function loss, genomic instability function gain, and abilities of cancer cell transcriptome and phenotype regulation [
37]. Future research is warranted to improve the outcomes. In addition to
TP53, other co-mutated genes, such as
PIK3CA, etc., are also detected. All these findings call for an intensive study of the role of these additional genetic abnormalities in disease evolution and how they might influence the efficacy of treatments.
Whether
RET fusion is mutually exclusive with other oncogenic drivers remains controversial. Recently, a study analyzing the fusion landscape in 33 cancer types highlighted the generally mutual exclusivity between fusions and mutations [
38]. Nonetheless, Wang et al. [
39] reported that one unique mutational signature in Chinese patients with NSCLC is associated with an increasing
EGFR mutation rate together with gene fusions, such as
RET and
ALK. In one retrospective analysis, concurrent
EGFR mutations were found in 7 of 47
RET-rearranged adenocarcinomas [
3]. In our study, patients with acquired RET-rearrangement after progression on EGFR TKIs were excluded due to the concern of the potential prognostic implications of frontline EGFR-TKI administration, and no co-existence of other driver-gene alteration appeared.
Previous studies have shown TCR repertoire diversity in the peripheral blood to be an indicator of prognosis, and high TCR repertoire diversity might indicate favorable outcomes [
23,
27,
28]. Our study supplemented the prognostic value of TCR repertoire diversity in
RET-driven lung cancers but disagree with the latter notion. Two explanations should be considered. First, although tumors with high TCR repertoire diversity are interpreted as biologically hot, two recent studies have indicated that intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8 T cells can be limited and variable, and there are bystander CD8 T cells [
40,
41]. Therefore, it seems that not all T cells are specific for tumor antigens in this study. Second, our data are limited in the dynamic analysis of the TCR repertoire during treatment and tumor evolution. As T cells can be easily isolated from patients’ blood without losing much of their functions [
24], TCR repertoire analysis can be utilized to stratify patients with long survival or screen ICI candidates in the future.
Importantly, our DCR of ICIs is superior to that presented before (60% vs. 25%), while PD-L1 expression is similar [
17,
42]. Although patients with selected druggable tumor alterations were considered as poor candidates for ICIs (for example,
EGFR-mutant and
ALK-rearranged lung cancers), and diverse efficacy of ICIs in
RET-positive patients was reported in previous studies [
16], a subgroup of patients exists who can benefit from ICIs as shown in our study. The challenge is how to precisely select these patients in future exploration. In this study, two patients with high PD-L1 expression experienced a satisfying response to ICIs. In a previous study,
CCDC6-RET was found to be immunogenic because of its peptide level [
38]. Predictive immuno-biomarkers are critical. Studies on overall immunogenicity and immune landscape are indispensable to strengthen the full understanding of ICIs in cancers with driver gene alterations.
However, the DCR of ICIs in our study seems to be driven by patients whose best objective response to this treatment was stable disease (4/6), and the median PFS is relatively short, revealing suboptimal outcomes of immune checkpoint inhibition. Notably, only one case received pemetrexed plus pembrolizumab as first-line therapy, a combination approved by the FDA based on data from the phase III KEYNOTE-189 trial, but yielded no response. Thus, considering evidence from several studies focusing on ICIs in oncogene-addicted NSCLCs, recently a summary of a multidisciplinary roundtable discussion recommended that ICIs should currently only be considered after exhaustion of targeted therapies and chemotherapies in these patients [
43].
Our observations can generate meaningful implications for clinical trial settings. Currently, all clinical trials of first-line ICIs, either single- or dual-agent, have excluded EGFR-mutant and ALK-rearranged lung cancers but included patients with RET-rearranged lung cancers. In our study, a trend towards inferior outcomes was observed in ICIs compared with chemotherapy. Thus, patients with RET rearrangement might not always be appropriate for first-line immunotherapy trials; they should consider the use of selective targeted therapies (if possible, since more specific and potent TKIs targeting RET are unavailable for most of our patients at the moment, and the efficacy of MKIs is disappointing) and chemotherapy instead until more specific biomarkers are found to distinguish responders and nonresponders to immunotherapy.
Our study has several limitations. First, dynamic changes in the TCR repertoire are lacking. Next, potential intratumor heterogeneity, evolution during the disease course, and treatment were not addressed by multiregional NGS. Future analysis of NGS data from larger databases is warranted. Moreover, our findings were limited to the relatively small sample size of patients with available treatment data and overlapping in each treatment group.
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