Selpercatinib benefit, with or without pembro, in first-line advanced RET fusion-positive NSCLC

Dr Herbert Ho Fung Loong - The Chinese University of Hong Kong, Hong Kong

At ESMO 2023 I had the opportunity to present our data on behalf of our co-investigators of the LIBRETTO-431 trial which is actually the first-line clinical trial of selpercatinib versus standard of care chemotherapy plus pembrolizumab in RET fusion-positive non-small cell lung cancer patients. We were very lucky that the abstract has been accepted as a plenary session and was presented on Saturday.

A bit of background about RET fusion-positive non-small cell lung cancer. It’s actually a relatively rare type of tumour, accounting for 2% of the population. In actual fact, we do know that, at least from prior evidence in this group of patients, the use of RET inhibitors in the original phase I clinical trial in treatment naïve patients has had good responses with response rates of up to about 80%. Having said that, the prevailing standard of care treatment right now for non-EGFR and non-ALK non-small cell lung cancer is the use of platinum-based chemotherapy plus pemetrexed plus pembrolizumab. This is based on the KEYNOTE-189 data. The results of those in terms of response and survival is certainly less than what we saw in the LIBRETTO-001 trial but there has been never any head-to-head comparison.

So the purpose of this trial really is to take a first-line approach, head-to-head comparison between selpercatinib, which is a selective RET inhibitor, against standard of care treatment to really try to position selpercatinib in the first-line space. So, for this particular clinical trial, as I’ve mentioned previously it’s a head-to-head comparison between selpercatinib and standard of care which, as I’ve mentioned already, also is chemotherapy plus pembrolizumab.

In this clinical trial we recruited patients of stage 3b, 3c as well as stage 4 non-squamous non-small cell lung cancer patients who are treatment naïve and have ECOG performance status of 0 to 2. They must have RET fusion identified either by next generation sequencing or PCR. We did allow patients with brain metastasis although patients with symptomatic brain metastasis were excluded. In terms of stratification we stratified the patients based on their geographical origin – East Asian versus non-East Asian – the presence or absence of brain metastasis. Also, given the fact that although the prevailing standard of care is the use of pembrolizumab together with chemotherapy, we also recognised the fact that not all patients are suitable to use pembrolizumab and there is also an investigator bias to use pembrolizumab or not to use in patients with actionable genomic drivers. So therefore in this situation we did allow patients to not have pembrolizumab in the trial but there’s a maximum cap of 20%. So at least 80% of the patients in the control group actually had to have had pembrolizumab at least planned in the intention to treat prior to randomisation.

Patients were randomised initially on a 1:1 and subsequently with an amendment became a 2:1 randomisation between selpercatinib and the control arm. In patients who actually progressed in the control arm they were given the opportunity to cross over to selpercatinib on disease progression.

The primary endpoint of this trial was progression free survival and it’s a gated dual primary endpoint of both the intention to treat pembrolizumab group as well as the overall population. The secondary endpoints include survival as well as intracranial responses and survival. We also looked at safety as well as patient reported outcomes.

This trial took place during the COVID pandemic and in total 261 patients were recruited into the trial. Over 100 centres from over 20 countries as well. I’m very pleased to say that in terms of the results the trial met its primary endpoint where the progression free survival of patients in the selpercatinib group exceeded those of the control group. The progression free survival in the selpercatinib group was 24.8 months versus 11.2 months in the control group. This was statistically significant with a hazard ratio of 0.46. This was also over a follow-up of a 19 month period. The same actually applied for patients who did not receive pembrolizumab and just the standard chemotherapy in the control.

So there is improvement in the progression free survival in the patients who were given selpercatinib in the front-line setting. Moreover, in terms of the response rates, patients in the selpercatinib group had a higher response rate of 83% and, most importantly, as well we also found that selpercatinib seemed to have not only efficacy in CNS metastasis but the possibility of preventing CNS metastasis for patients who did not have baseline brain metastasis. Incidentally, 20% of patients recruited into the clinical trial had brain metastasis at baseline. So for the patients who did not have baseline brain metastasis, after being treated with selpercatinib for 12 months only about 1.1% of these patients developed brain metastasis as opposed to 14.7% of the patients in the control group.

In terms of the safety profile, it is what we have seen in our prior experiences with selpercatinib in the LIBRETTO-001 trial as well as given the fact that the drug is approved in over 20 jurisdictions around the world. We have good clinical experience. The most common toxicities were AST/ALT changes, there were peripheral oedema, there were hypertension and all of these were well controlled with dose interruption as well as dose changes. As expected, the chemotherapy arm, or the control arm, had the toxicities of mainly myelosuppression.

Lastly, I think it’s very important for us to also focus on the feelings of the patients in terms of the patient-reported outcomes. Certainly, in terms of deterioration of physical function as well as worsening of symptoms, selpercatinib patients actually had a delay in those two parameters as well.

So, overall, this clinical trial has confirmed the fact that selpercatinib is, of course, a useful drug in RET fusion positive non-small cell lung cancer. Secondly, it should be positioned in the first-line setting. The difficulty, of course, is to identify these patients and certainly this also calls for the need for up-front next generation sequencing for our patients so we are therefore able to identify these patients and treat them with the appropriate treatment which does give them more than doubling in terms of progression free survival.