American Society of Clinical Oncology Annual Meeting 2024

Eli Lilly presented data from research studies of the RET inhibitor Retevmo (selpercatinib)

• Intracranial outcomes of 1L selpercatinib in advanced RET fusion-positive NSCLC: LIBRETTO-431 study. Presented by Maurice Perol, Department of Medical Oncology, Léon-Bérard Cancer Center, Lyon, France. Abstract Number: 8547The LIBRETTO-431 (NCT04194944), is a phase 3 trial that investigates and compares the activity of the RET inhibitor selpercatinib given as first line to platinum-based chemotherapy +/- pembrolizumab (pembro). A total of 192 patients were evaluated. Selpercatinib delayed intracranial progression in advanced RET+ NSCLC patients with or without baseline brain metastasis and achieved higher intracranial response rates compared to chemotherapy + pembrolizumab. These data further support selpercatinib as the preferred first-line regimen in patients with advanced RET+ NSCLC. More information here.
• Health-related quality of life (HRQoL) and symptoms in LIBRETTO-431 patients with RET fusion-positive advanced non-small-cell lung cancer (NSCLC). Presented by Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, China. Abstract number 11068Selpercatinib significantly delayed the time to confirmed deterioration (TTCD) of NSCLC symptoms (cough, dyspnea, pain, fatigue, poor appetite) and improved physical function compared to control in this patient population after 1 year of treatment. The findings were consistent with the favorable efficacy of selpercatinib compared with platinum-based chemotherapy + pembro and further support first line use of selpercatinib in this population. More information here.
• LIBRETTO-432: A phase 3 study of adjuvant selpercatinib or placebo in stage IB-IIIA RET fusion-positive (RET+) NSCLC. Presented by Jonathan W. Goldman, David Geffen School of Medicine at University of California, Los Angeles, CA.Around 30% of RET NSCLC patients present with early stage IB-IIIA disease. For early-stage disease, standard treatment options are surgery w/wo chemotherapy and/or immunotherapy. Recent phase III trials in other oncogene driven NSCLC such as EGFR mutant NSCLC, have shown the benefits of the treatment with specific targeted inhibitors (ADAURA and ALINA). LIBRETTO-432 is a phase III, trial evaluating efficacy and safety of the RET inhibitor selpercatinib compared to placebo in patients with RET+ stage IB-IIIA NSCLC (NCT04819100). Recruitment is ongoing, with enrollment across ~170 sites and 30 countries. Results from this trial will further inform the value of RET inhibition for early-stage RET NSCLC patients. Clinical trial information: NCT04819100. More information here and here.

Dr. Mihaela Aldea presented data on the anti-VEGF antibody bevacizumab in combination with chemotherapy for treating patients with advanced RET+ NSCLC

Dr. Mihaela Aldea from the Gustave Roussy, Department of Medical Oncology, Paris Saclay University, Villejuif, France, presented data from a retrospective study comparing the efficacy of the treatment with either a platinum-doublet chemotherapy with immunotherapy (anti-PD-L(1) agents) or a non-platinum chemotherapy, with or without the addition of the anti-VEGF antibody bevacizumab (Bev) in patients with RET NSCLC (185 patients).

The objective response and the median progression-free survival was significantly longer in the group of patients receiving platinum-doublet chemotherapy with immunotherapy with the addition of bevacizumab with 55% vs 47% (p=0.7), and 17 months vs. 8.8 months (p=0.018) respectively.

The median overall survival was 51.4 months for the RET patients treated with platinum-doublet chemotherapy with immunotherapy with the addition of bevacizumab compared to 38.7 months for patients treated with platinum-doublet chemotherapy with immunotherapy only (p=0.89).

For patients treated with non-platinum chemotherapy with the addition of bevacizumab, the objective response was 13% versus 25% for patients treated with non-platinum chemotherapy only (p=0.6). The median progression-free survival was significantly longer 2.4 months versus 4.1 months (p=0.06), and median OS was 12.1 months versus 39 months (p=0.06).

Conclusions: Bevacizumab with platinum-doublet chemotherapy seems to outperform platinum-doublet with or without immunotherapy in progression-free survival. Prospective research is needed to evaluate the extent of bevacizumab’s benefit for RET+ NSCLC. Abstract and poster information here.

Ellipses Pharma and Dr. Elena Garralda presented some clinical data of the second-generation RET inhibitor EP0031 in RET NSCLC

EP0031 (A400/KL590586) is a next-generation RET inhibitor that is potentially more effective against common RET alterations, including those that cause resistance. This treatment also shows better ability to reach the brain. Dr. Elena Garralda from Vall d’Hebron University Hospital and the Vall d’Hebron Institute of Oncology in Barcelona, Spain, shared early results from a study testing EP0031 in patients with RET-altered non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), or other RET-altered tumors.

As of December 13, 2023, 27 patients (average age 58) had joined the study. This group included:

• 14 patients with NSCLC (12 had been treated with a RET inhibitor before)
• 8 patients with MTC (5 had been treated with a RET inhibitor before)
• 5 patients with other RET-altered tumors (3 had been treated with a RET inhibitor before)

Results so far:

• Out of 8 NSCLC patients evaluated, 1 patient who had not received prior RET inhibitor treatment had a complete response. Among the 7 patients previously treated with RET inhibitors, 4 had partial responses, and 2 had complete responses in the brain.
• Among 8 MTC patients evaluated, 2 patients who had not received prior RET inhibitor treatment had partial responses, and 1 had stable disease. Of the 5 patients previously treated with RET inhibitors, 2 achieved stable disease.
• Among 5 patients with other RET-altered tumors, 2 patients (1 with pancreatic cancer and 1 with papillary thyroid cancer) had stable disease after prior treatment with RET inhibitors.

The most common mild to moderate side effects included constipation, headache, increased liver enzymes, anemia, blurred vision, and dizziness. Serious side effects were rare and included low sodium levels, anemia, high blood pressure, and diarrhea.

Conclusions: EP0031 shows promise in treating advanced cancers with RET alterations, even in cancer patients who have previously been treated with and progressed on other RET inhibitors. Clinical trial information: NCT05443126.

Dr. Tejas Patil presented the amivantamab clinical trial for treating patients with RET+ NSCLC who have progressed on RET inhibitors

Dr. Tejas Patil from the University of Colorado Comprehensive Cancer Center, Aurora, CO, presented the phase 1b / 2 study of amivantamab in combination with tyrosine kinase inhibitor (TKIs) among participants with advanced NSCLC harboring ALK, ROS1, and RETgene fusions progressing on FDA-approved TKIs for their respective oncogene.

Amivantamab is a bispecific antibody that targets the epidermal growth factor receptor (EGFR) and MET. In many cases patients who become resistant to TKI therapies including RET inhibitors present increased activation of MET and EGFR as a bypass signaling mechanism that allows these cancer cells to circumvent the selective pressure from the therapy.

A total of 16 to 35 evaluable patients, depending on the safety of the tested treatments in the dose escalation phase, are expected to be accrued to this study.

Clinical trial information: NCT05845671.

Dr. Anwen Xiong presented some clinical data of the RET inhibitor SY-5007 in RET NSCLC

Dr. Anwen Xiong from the Department of Medical Oncology, Shanghai Pulmonary Hospital, Cancer Institute, Tongji University School of Medicine, Shanghai, China, presented some updated data of the clinical trial investigating the RET inhibitor SY-5007

As of January 16, 2024, the trial enrolled 105 patients. The RET inhibitor SY-5007 demonstrated high efficacy with an objective response rate of 77.1% (95% CI 67.9-84.8) and a disease control rate of 83.8% (95% CI 75.3-90.3). In pre-treated patients (cohort 2, n=49), SY-5007 exhibited an objective response rate of 69.4% (95% CI 54.6-81.7) and a disease control rate of 89.8% (95% CI 77.8-96.6). Median progression free survival or overall survival were not reached. The RET inhibitor SY-5007 also showed great intracranial responses in patients with brain metastases.

Treatment-related adverse events (TRAEs) were reported in 96.2% of patients, with common events (≥ 30%) including increased aspartate aminotransferase (AST), increased alanine transaminase (ALT), decreased neutrophil count, decreased white blood cell count and decreased platelet count. Grade ≥ 3 TRAEs and treatment-related serious adverse events were observed in 42.9% and 10.5% of patients. TRAE-induced dose interruption and dose reduction occurred in 39.0% and 23.8% of patients, respectively. TRAEs led to SY-5007 discontinuation in two patients (1.9%), with no deaths due to TRAE.

Conclusions: SY-5007 demonstrated promising efficacy for advanced NSCLC with positive RET. Clinical trial information: NCT05278364.