Retevmo Improves Progression-Free Survival in Patients with RET-Fusion Positive NSCLC

Retevmo (selpercatinib) versus chemotherapy with or without Keytruda (pembrolizumab) as first-line treatment improved progression-free survival (PFS, length of time from the start of treatment until after when the disease does not worsen) in patients with RET fusion-positive non-small cell lung cancer (NSCLC), according to data from a recent phase 3 trial presented at the 2023 ESMO Congress.

In the phase 3 LIBRETTO-431 trial, 159 patients received Retevmo and 102 patients received carboplatin plus pemetrexed (two types of chemotherapy drugs) with or without Keytruda. The purpose of the trial was for investigators to define the best frontline regimen for this patient population. The trial enrolled patients with stage 3B to 3C or stage 4 nonsquamous NSCLC with RET fusions.

The highly selective and potent RET inhibitor, Retevmo, is indicated for adult patients with locally advanced or metastatic NSCLC who have a RET gene fusion with the regulatory decision based on data from the phase 1/2 LIBRETTO-001 trial.

The median age of patients across the Retevmo and control arms was 61 years, with slightly more than half of patients being female and most being never smokers. More than half of patients were Asian. In the Retevmo arm, 58.1% of patients were enrolled to the trial in an East Asian region and 41.9% were enrolled in a Non-East Asia region; in the control arm, these rates were 49.4% and 50.6%, respectively.

At a median follow-up of approximately 19 months in the intention-to-treat (ITT, entire study population)/Keytruda population, the median PFS in the Retevmo arm of 129 patients was 24.8 months versus 11.2 months in the control arm of 83 patients.

In the ITT population, and with a median follow-up of approximately 18 months, the median PFS in the Retevmo and control arms were 24.8 months and 11.2 months, respectively.

With these improvements, the primary end points of the trial were met, said Herbert H. Loong during the presentation of the data. Loong is a clinical associate professor in the Department of Clinical Oncology and deputy medical director of the Phase I Clinical Trials Centre at The Chinese University of Hong Kong.

“(Retevmo) should be considered as a first-line standard of care (SOC) in RET fusion-positive, advanced NSCLC,” Loong said. “These results reinforce the importance of genetic testing to identify RET fusions at the time of diagnosis, to inform initial therapy.”

Key stratification factors included geography (East Asian versus non-East Asian), brain metastases (present versus absent/unknown) and investigator’s choice of treatment with Keytruda.

“The prevailing treatment of choice such as these included in the study as mentioned previously is platinum plus pemetrexed plus (Keytruda). We also understand that it is sometimes of difficulty to obtain (Keytruda) in some of these patients as well as suitability to use (Keytruda). So, within this particular clinical trial, we did allow for patients an investigator’s choice of whether or not they should be treated with (Keytruda) if they were to be randomized into the control arm,” Loong explained. “Within the protocol, this is specified to include at least 80% of the patients with the intention to be treated with (Keytruda) in the control arm, and this is known as the ITT/(Keytruda) population.”

The trial’s primary endpoint (main result measured at the end of a study to see if treatment worked) was PFS in the ITT/Keytruda and ITT populations.

Secondary end points included overall survival (OS, length of time from diagnosis or start of treatment when a patient remains alive), overall response rate (ORR, percentage of patients in the study who have a partial or complete response to treatment), and duration of response (DOR, length of time that a disease responds to treatment without progressing.

According to the data, Retevmo had a median PFS of 22 months and an ORR of 84%. Responses also proved to be more durable with Retevmo versus the control regimen, with a median DOR of 24.2 months and 11.5 months, respectively.

“The prevailing SOC of treatment for patients in first-line NSCLC is platinum (chemotherapy) plus pemetrexed plus (Keytruda). This combination, of course, is established in the first-line treatment setting based on the KEYNOTE-189 study,” Loong said. Data from this trial showed that the combination elicited an ORR of 47.6% and resulted in a median PFS of 8.8 months.

Notably, those in the control arm had the option to cross over to receive Retevmo upon disease progression.

“Of note is that in the control group, out of the 68 patients who discontinued treatment, 42 actually subsequently crossed over to (Retevmo) as per what was allowed in the study protocol,” Loong said.

“OS data (are) currently immature, with a censoring rate of (approximately) 80%; it is also kind of confounded by the fact that within the protocol, there were 61% of patients who crossed over,” he added.

Key baseline characteristics were noted to be well balanced between the treatment arms.

“What I would specifically like to highlight is that about 20% — again, well balanced in both arms of patients — had brain metastases at baseline,” Loong said.

Data from the preplanned subgroup analysis showed consistent PFS benefit with Retevmo versus the control regimen in all subsets.

“Of note is also the fact that the positivity or negativity of PD-L1 expression in tumors did not seem to have any effect on whether patients favored Retevmo or the control, and all these patients seemed to favor Retevmo,” Loong added.

The median time on the RET inhibitor was approximately 70% longer than the control regimen, at 16.7 months versus 9.8 months, respectively.

Any-grade side effects occurred in all 158 patients in the Retevmo arm vs 99% of the 98 patients in the control arm. These side effects were grade 3 or higher for 70.3% and 57.1% of patients, respectively. In the Retevmo arm, side effects led to dose adjustments and reductions in 77.8% and 51.3% of patients, respectively. In the control arm, these rates were 75.5% and 28.6%, respectively. Toxicities resulted in treatment discontinuation for 10.1% versus 2% of patients, respectively.

“In terms of the safety profile, the most common (side effects) that were seen in patients treated with Retevmo included (aspartate aminotransferase increase, enzyme mostly found in the liver), (alanine transaminase increase, enzyme found in the liver), (high blood pressure), diarrhea and edema (swelling caused by excess fluid trapped in body’s tissues), and these were consistent with what we’ve seen in prior clinical trials, including LIBRETTO-001, as well as in our clinical practice,” Loong said. “Most of the (side effects) were essentially well managed with dose modifications and dose reductions in the patients who were treated.”

Specifically, the most common any-grade toxicities experienced with Retevmo and the control regimen included increased aspartate aminotransferase (49% versus 39%, respectively), increased alanine aminotransferase (38% versus 37%), high blood pressure (28% versus 4%), diarrhea (43% versus 23%), edema (39% versus 28%), dry mouth (39% versus 6%), increased blood bilirubin (36% versus 1%), rash (31% versus 29%), fatigue (29% versus 45%), thrombocytopenia (23% versus 22%), leukopenia (24% versus 26%), abdominal pain (25% versus 17%), increased blood creatinine (23% versus 16%), neutropenia (21% versus 17%), constipation (22% versus 39%), QT prolongation (11% versus 1%), reduced appetite (17% versus 32%), pyrexia (13% versus 24%), vomiting (13% versus 23%), nausea (13% versus 43%), anemia (10% versus 48%) and pruritus (10% versus 22%).

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