Clinical Trials of Targeted Therapies in RET-Rearranged NSCLC

RET (rearrangement during transfection) rearrangements occur in 1% to 2% of cases of non–small-cell lung cancer (NSCLC).¹ The effects of multitarget kinase inhibitors have been shown to be limited.¹ Consequently, a number of selective next-generation RET inhibitors are under investigation. Retevmo (selpercatinib; Eli Lilly) is a highly selective tyrosine kinase inhibitor approved under an accelerated approval and indicated for adult patients with metastatic RET fusion–positive NSCLC.² Continued approval may be contingent upon confirming clinical benefit in clinical trials.

Selpercatinib is being studied in the ongoing LIBRETTO-001 trial (NCT03157128) that includes 105 patients with RET fusion–positive NSCLC who have metastatic disease.² Patients were previously treated with platinum-based chemotherapy and were treated with a median of 3 previous systemic regimens²; 55% of patients had previously been treated with anti–PD-1 or PD-L1 therapies and 48% had been pretreated with ≥1 multikinase inhibitors.³ The median age of enrolled patients is 61 years.² The overall response rate (ORR) is 64% (95% confidence interval [CI], 54%-73%),² which was similar regardless of previous treatment.³ The median duration of response (DOR) is 17.5 months (95% CI, 12-not estimable [NE]).² At baseline, 11 patients had central nervous system metastases, and the ORR is 91% (95% CI, 59%-100%) among these patients.^2,3 The study has also included 39 patients who are treatment-naïve.² Among this subpopulation, the ORR is 85% (95% CI, 70%-94%), and the median DOR is not estimable. The safety analysis of selpercatinib includes 702 patients, 65% of whom have been exposed for ≥6 months and 34% of whom have been exposed for >1 year. Serious adverse events have occurred in 33% of patients, 5% of patients permanently discontinued related to an adverse reaction, 42% have required dosage interruption, and 31% have had a dose reduction. The most commonly reported adverse events that have occurred in >15% of patients have included dry mouth, diarrhea, constipation, nausea, abdominal pain, hypertension, fatigue, edema, rash, headache, cough, dyspnea, and prolonged QT interval. The most common grade ≥3 adverse events have been diarrhea (3.4%), hypertension (18%), and prolonged QT interval (4%).

Pralsetinib is a recently approved RET inhibitor that was being studied in a phase 1/2 dose-escalation and expansion study (NCT0307385) of 132 of 354 patients with locally advanced or metastatic NSCLC with RET fusion or mutation.⁴ The median age of participants was 60 years, and approximately 42% had brain metastases. Previous treatment regimens included chemotherapy (71%), PD-L1 inhibitor (36%), and chemotherapy plus PD-L1 inhibitor (31%). Of patients with evaluable response (N = 116), the ORR was 57% (95% CI, 46%-68%), including 6% with a complete response, and the effects occur regardless of previous therapies. The median DOR was not reached (95% CI, 15.2 months-NE). Among 27 treatment-naïve patients, the ORR is 70% (95% CI, 50%-86%) with 11% experiencing a complete response.⁴

Pralsetinib is well-tolerated, and the most commonly reported adverse events that have occurred in >25% of patients have included fatigue, constipation, musculoskeletal pain, and hypertension. Grade ≥3 adverse events occurred in 2.5% of patients.⁴ Pralsetinib is also being studied in an ongoing phase 3, open-label, randomized study (NCT04222972) of 250 patients with advanced or metastatic NSCLC who have had no previous treatment for metastatic disease.⁵ Patients are being randomized to either pralsetinib or platinum-based chemotherapy ± pembrolizumab (Keytruda; Merck). The primary end point is progression-free survival, and secondary end points include ORR, overall survival, safety/tolerability, clinical benefit and disease control rate, DOR, and time to intracranial progression and response rate.⁵

In summary, the study results of selpercatinib and pralsetinib are encouraging for patients with RET-rearranged NSCLC and are clearly an advance over multikinase inhibitors.

References

1. 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.
2. Retevmo (selpercatinib) capsules, for oral use [package insert]. Indianapolis, IN: Eli Lilly and Company; May 2020.
3. Eli Lilly and Company. Lilly announces positive results for selpercatinib (LOXO-292), demonstrating a 68 percent objective response rate and sustained durability in heavily pretreated RET fusion-positive non-small cell lung cancer. September 9, 2019. https://investor.lilly.com/news-releases/news-release-details/lilly-announces-positive-results-selpercatinib-loxo-292. Accessed July 30, 2020.
4. GAVRETO™ (pralsetinib) Prescribing Information (US). Blueprint Medicines Corporation, Cambridge, Massachusetts, USA; September 2020.
5. Besse B, Felip E, Clifford C, et al. AcceleRET lung: a phase 3 study of first-line pralsetinib in patients with RET fusion+ advanced/metastatic non-small-cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15). Abstract TPS9633.