New RET Research Advances from IASLC WCLC 2026

First author: Can Cui
Institution: Memorial Sloan Kettering Cancer Center

A new analysis of the phase 3 LIBRETTO-431 study provides important insights into the role of chemotherapy and immunotherapy in people with RET fusion-positive non-small cell lung cancer (NSCLC). The analysis included 102 patients: 83 received chemoimmunotherapy and 19 received chemotherapy alone. The two groups were similar in smoking history, PD-L1 status, and the presence of brain metastases at baseline. Median progression-free survival (PFS) was 11.0 months with chemoimmunotherapy and was not reached with chemotherapy alone, with no significant difference between the groups (p=0.8). Overall survival (OS) was not reached in either group, and there was also no significant difference in OS (p>0.9).

Conclusions:

In this analysis, outcomes with first-line chemoimmunotherapy and chemotherapy alone were not significantly different in patients with advanced RET fusion-positive lung cancer. These findings suggest that adding pembrolizumab to chemotherapy may not provide additional benefit when chemotherapy is used to treat RET-driven tumors. However, the chemotherapy-alone group was relatively small, so these findings should be interpreted with caution.

These results were published very recently here. Find more about this study here.

First author: Arianna Marinello
Institution: Institut Gustave Roussy

This international retrospective study used data from the RET-MAP registry, which included 588 RET-positive patients from 52 institutions. Of these, 45 patients (7.7%) had non-LUAD histology, most commonly large-cell neuroendocrine carcinoma (LCNEC) and adenosquamous carcinoma. Non-LUAD tumors were more likely to have brain metastases at diagnosis than LUAD (38% vs. 21%). Genomic analyses also showed increased metabolic activity and enrichment of proliferative and oncogenic pathways in non-LUAD tumors, including E2F signaling, MYC targets, PI3K/mTOR signaling, and DNA repair pathways.

Among 411 patients treated with selective RET inhibitors (SRI), non-LUAD histology was independently associated with shorter progression-free survival (PFS) and overall survival (OS). Similarly, among 272 patients who received first-line chemotherapy, non-LUAD histology remained an independent adverse prognostic factor. However, an interesting finding emerged among patients with LCNEC: 6 of 8 patients (75%) responded to selective RET inhibitors, and their survival outcomes were comparable to those observed in patients with LUAD.

Conclusions:

These findings suggest that RET-positive non-LUAD NSCLC represents a rare but biologically distinct group with more aggressive features and poorer outcomes overall. Importantly, the responses seen with selective RET inhibitors highlight the importance of molecular testing for RET fusions even in patients whose tumors do not have the typical adenocarcinoma histology. Patients with large cell neuroendocrine carcinoma showed encouraging responses to selective RET inhibitors, with survival outcomes comparable to LUAD.

First author: X-N. Yang
Institution: Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China 

New data from the phase 3 LIBRETTO-432 trial provide further support for using selpercatinib in patients with early-stage RET fusion-positive non-small cell lung cancer (NSCLC). The analysis included 73 Chinese patients with Stage IB–IIIA RET+ NSCLC, who received either selpercatinib or placebo for up to 3 years after surgery or other curative-intent treatment. The results were encouraging: no patients receiving selpercatinib experienced a recurrence or death during the analysis period. Among patients with Stage II–IIIA disease, 2-year event-free survival (EFS) was 100% with selpercatinib vs. 59.5% with placebo, while among all Stage IB–IIIA patients, 2-year EFS was 100% vs. 70.8%, respectively. Only one death occurred, in the placebo group.

The safety profile of selpercatinib was consistent with previous experience in RET+ NSCLC, with increased ALT and AST liver enzymes among the most common adverse events. Importantly, these findings were consistent with the results from the overall global LIBRETTO-432 population, which previously showed an approximately 83% reduction in the risk of recurrence or death with adjuvant selpercatinib.

Conclusions:

Overall, these results add to growing evidence for using selpercatinib in patients with early-stage RET fusion-positive NSCLC.

First author: W.J. Phillips
Institution: University of Colorado, Anschutz, Aurora, Colorado, USA 

Researchers from the University of Colorado conducted a study and evaluated 46 patients treated with selpercatinib or pralsetinib. 19 patients (37%) required a dose reduction, most commonly because of side effects such as low blood counts or liver inflammation. Importantly, progression-free survival (PFS) was similar between patients who had a dose reduction and those who did not: 13.7 months vs. 14.6 months. Time to the next treatment was also similar (23.7 vs. 19.3 months), and dose reduction was not significantly associated with worse PFS or a shorter time to the next treatment.

The researchers also found no significant increase in brain progression among patients who had their dose reduced. An additional analysis designed to account for potential bias produced similar results. 

Conclusions:

Overall, these findings suggest that reducing the dose of a RET inhibitor when needed to manage side effects may not necessarily compromise its effectiveness. For patients experiencing significant side effects, these results may provide reassurance that adjusting the dose under the guidance of their oncology team can be an option to help them remain on treatment. However, this was a small retrospective study of 46 patients, and larger studies are needed to confirm these findings.

Important note: Never reduce, skip, or change the dose of your RET inhibitor without first discussing it with your oncology team. Changing your dose on your own could affect the effectiveness of your treatment. Your doctor can help determine whether a dose adjustment is appropriate and how to do so safely.

First author: Jeffrey Zhu
Institution: Icahn School of Medicine at Mount Sinai

This study analyzed 514 patients with molecular profiling from the prospective, multi-institutional IELCART cohort who underwent surgery for clinical stage IA lung tumors ≤30 mm. Researchers identified 17 patients (3.3%) with a RET, ALK, or ROS1 fusion, including 8 ALK (1.5%), 6 ROS1 (1.2%), and 3 RET fusions (0.6%). Patients with these fusion drivers were younger than those without a fusion (62 vs. 71 years) and were substantially more likely to have never smoked (65% vs. 24%). They were also less likely to have COPD and more likely to have tumors located in the lower lobes.

Importantly, the study found that post-surgical outcomes and survival appeared favorable among patients with fusion-driven lung cancers and were consistent with outcomes observed in other patients undergoing surgery for early-stage NSCLC. After adjusting for age, sex, smoking status, smoking exposure, and nodule size, there were no significant differences in overall survival between patients with fusion-driven tumors and those without these fusions. These findings suggest that RET, ALK, and ROS1 fusions can be present even in very small, early-stage lung cancers and may be particularly relevant in younger people and those who have never smoked.

Conclusions:

These findings highlight that targetable RET, ALK, and ROS1 fusions can be found in small, early-stage lung cancers, including tumors in people who may not fit traditional profiles for lung cancer screening. The authors emphasize that early detection remains critical for achieving the best chance of cure, regardless of the tumor’s molecular alteration.

First author: H-Y. Deng
Institution: West China Hospital, Sichuan University, Chengdu, China 

This study explored whether surgery could be safely used after treatment with selective RET inhibitors in patients with advanced RET fusion-positive NSCLC. Researchers retrospectively analyzed 17 patients treated at West China Hospital between 2022 and 2025. Patients received a RET inhibitor for an average of 12 months before undergoing salvage surgery, and all patients recovered without major complications or 30-day deaths. Notably, 47.1% achieved a complete pathological response, meaning no cancer was detected in the surgical specimen, while 76.5% achieved a major pathological response.

After a median follow-up of 26 months, the estimated 3-year progression-free survival (PFS) was 75% and overall survival (OS) was 100% following surgery. These results suggest that, in carefully selected patients with advanced RET fusion-positive NSCLC who respond well to RET-targeted therapy, surgery may be a feasible additional treatment strategy. However, because this was a small, retrospective study of only 17 patients from a single center, larger prospective studies are needed to determine which patients are most likely to benefit from salvage surgery and whether this approach can improve long-term outcomes. 

Conclusions:

These findings suggest that salvage surgery may be a feasible treatment option for carefully selected patients with advanced RET fusion-positive NSCLC who respond well to RET-targeted therapy. The favorable PFS and OS observed after surgery are encouraging, but the results should be interpreted cautiously because the study included only 17 patients and was retrospective and conducted at a single center. Larger prospective studies are needed to determine which patients may benefit most from surgery after RET inhibitor treatment and whether this approach can improve long-term outcomes.

First author: N.N. Mederos Alfonso
Institution: Lausanne University Hospital, Lausanne, Switzerland 

A case series explored whether adding chemotherapy to an ongoing targeted therapy could help patients with RET- or ROS1-rearranged NSCLC whose disease progressed without an identifiable resistance mechanism. The researchers described three patients who received platinum-based chemotherapy while continuing their targeted therapy.

Two patients had RET-positive lung cancer. One experienced rapid progression after only four weeks of selpercatinib, but achieved a partial response after chemotherapy was added. The second had remained on targeted therapy for approximately three years before progressing and subsequently achieved a complete response after chemotherapy was added. A third patient with ROS1-positive disease also achieved a complete response after chemotherapy was combined with lorlatinib.

These cases highlight the possibility that resistance to targeted therapies may involve multiple cancer cell populations, including some that remain dependent on the oncogenic driver and others that develop alternative mechanisms of growth. In this setting, continuing targeted therapy while adding chemotherapy could potentially address different tumor populations at the same time. Prospective clinical trials are needed to determine whether combining chemotherapy with continued RET-targeted therapy can improve outcomes after progression and which patients are most likely to benefit.

Conclusions:

These cases suggest that continuing RET-targeted therapy while adding chemotherapy may be a potential treatment strategy for some patients whose cancer progresses without an identifiable resistance mechanism. Prospective clinical trials are needed to confirm these findings.