For RET-positive lung cancer patients whose cancer has progressed on a RET inhibitor, new research offers a promising direction for what comes next.
A new clinical study results show that treating patients with RET fusion-positive non-small cell lung cancer (NSCLC) after their cancer progresses on a RET inhibitor remains a significant challenge. A recent real-world study from MD Anderson suggests that RET NSCLC patients who continued their RET inhibitor while adding chemotherapy after disease progression experienced better outcomes than those who switched to chemotherapy plus immunotherapy. Among 12 patients reviewed, median progression-free survival was 7.8 months with chemotherapy plus a RET inhibitor compared with 3.5 months for chemotherapy plus immunotherapy. These findings support further larger studies and investigation of continuing RET-targeted therapy beyond progression in selected patients.
Key Takeaways
Detailed Results From The Study:
Title: Clinical Activity of RET Tyrosine Kinase Inhibitor (TKI) plus Chemotherapy after Progression on a RET TKI in a RET Fusion–Positive Non–Small Cell Lung Cancer Real-World Cohort: A Brief Report.
About the Study
This retrospective real-world study was led by Dr. Alvaro Guimaraes Paula from Dr. Heymach’s team at MD Anderson. The investigators wanted to determine whether patients who continued their RET inhibitor while adding chemotherapy had better outcomes than those who switched to chemotherapy plus immunotherapy after their cancer progressed on RET-targeted therapy.
Study Results
The study included 12 patients with RET fusion-positive NSCLC, 8 patients received chemotherapy while continuing their RET inhibitor and 4 patients received chemotherapy plus immunotherapy.
- Better progression-free survival
Patients treated with chemotherapy plus a RET inhibitor remained free from disease progression for a median of:
- 7.8 months with chemo + RET inhibitor
- 3.5 months with chemo + immunotherapy
- Higher response rate
The overall response rate was 38% for the chemo + RET inhibitor group, with 3 patients achieving partial response (including 1 metabolic complete response meaning no metabolically active cancer was detected on PET imaging), 4 patients (50%) stable disease (including 3 with tumor shrinkage) and 1 patient had disease progression.
In the chemo + immunotherapy group 1 patient achieved partial response (25%), 2 patients had stable disease (50%), and the last one had disease progression
There was a modest but nonsignificant overall survival benefit for the chemotherapy plus a RET inhibitor group (median OS, 14.1 months) versus the chemotherapy plus immunotherapy group (estimated median OS, 12.6 months).
Safety
Patients who received chemotherapy while continuing a RET inhibitor experienced more serious side effects than those treated with chemotherapy plus immunotherapy. Six of the eight patients (75%) in the chemotherapy plus RET inhibitor group had at least one severe (grade 3) treatment-related side effect, most commonly febrile neutropenia (a serious infection risk caused by very low white blood cell counts), and one patient discontinued the RET inhibitor because of severe swelling (edema).
In the chemotherapy plus immunotherapy group, 1 patient (25%) developed a grade 3 adverse event, febrile neutropenia. Importantly, no life-threatening (grade 4) side effects or treatment-related deaths were reported in either treatment group.
Study limitations
This was a small, retrospective study from a single cancer center. Because of these limitations, larger prospective clinical trials are needed to confirm these findings.
Conclusions
In this study, patients who continued their RET inhibitor while adding chemotherapy experienced longer progression-free survival than those who received the current standard treatment of chemotherapy with or without immunotherapy. However, the combination of chemotherapy and a RET inhibitor was also associated with a higher rate of grade 3 (serious) treatment-related adverse events.
Although this approach is not currently approved by the FDA or other agencies and requires confirmation in larger clinical trials, the findings support a strategy already used by some physicians and are consistent with treatment approaches that have shown benefit in other oncogene-driven lung cancers, such as EGFR- and ALK-positive NSCLC.
