Paolo Ascierto, MD, National Cancer Institute, Naples, Italy, discusses results from the parallel-arm, randomized phase 2 SECOMBIT trial, evaluating the ideal sequential strategy of targeted therapy and immunotherapy for patients with BRAFV600-mutated melanoma.

The strategies explored were first-line combination therapy of encorafenib and binimetinib with a switch to ipilimumab and nivolumab at progression (Arm A), first-line combination therapy of ipilimumab and nivolumab with a switch to encorafenib and binimetinib at progression (Arm B), and a “sandwich” strategy: induction on encorafenib and binimetinib, followed by a planned switch to ipilimumab and nivolumab at 8 weeks, and then a return to encorafenib and binimetinib after progression (Arm C).

The 4-year follow-up data confirms the positive trends seen in Arms B and C. Additionally, certain benefits were seen in subgroups of patients with low interferon gamma cytokine and JAK mutations.

This data was presented at the 2022 European Society for Medical Oncology (ESMO) Congress in Paris, France.

Transcript:

I'm Paolo Ascierto. I'm a medical oncologist and I'm the chief of the Department of Skin Cancer, Cancer Immunotherapy Development Therapeutics at the National Cancer Institute, Naples, Italy.

The SECOMBIT study is a randomized phase 2 study, evaluating the sequence of targeted therapy and immunotherapy for metastatic melanoma, BRAF-mutated. We enrolled patients in 3 arms, on a 1:1:1 basis.

The first arm is combination targeted therapy, with encorafenib and binimetinib first and then, in case of progression, combination immunotherapy with ipilimumab and nivolumab. In the second arm, patients received ipilimumab and nivolumab, and in case of progression, encorafenib and binimetinib.

The third arm, we called the “sandwich” arm. Why “sandwich”? Because the immunotherapy is put in the middle of 2 courses of targeted therapy. The first is an induction, 8 weeks with encorafenib and binimetinib, then at response, we switched to ipilimumab-nivolumab and then, in case of progression, again, encorafenib and binimetinib. The main end point was overall survival.

At the 2022 ESMO Congress, we presented an update at 4 years with a minimum follow-up of 43 months at the data cutoff date of June 30 of this year, and we showed the updated total progression-free survival and overall survivor, and some preliminary biomarkers data.

The total progression-free survival confirmed the better trend of the arms B and C, where immunotherapy was given first, compared to the arm where targeted therapy was given first. So, there is an important gap between the arms where immunotherapy was first and targeted therapy was first. The hazard ratio was interesting, 0.60 and significant. It's an exploratory hazard ratio because the trial was not designed to compare, but it's still interesting and does confirm what we have already seen with a minimum follow up of 3 years.

In terms of overall survival, the same. With this confirmation data, the gap is less but still important than, again, confirmed role of immunotherapy as first. Even in terms of overall survival, which is the main end point.

We also did an update of the subgroup analysis and in the elevated LDH patients, still, the arms where immunotherapy was given first, and mainly in the sandwich arm, they did better and this is interesting because it may be a possible approach in patients with elevated LDH to start with a short induction with target therapy, then switch to immunotherapy. Same for the patients with high tumor burden, defined as patients with more than three sites of metastasis. In this case, in both B and C arms, where immunotherapy was given first, went better than target therapy.

We presented preliminary data on biomarkers, and we present the preliminary data about the cytokine evaluation serum on about 80 samples. And, also, we presented the next generation sequencing where we evaluated 400 genes in 93 samples and the samples were from the patients from the different arm and also from the different sequence. And the most interesting data that we found, the tumor mutation burden was important. It was important mainly in arms A and B. So, combination of targeted therapies first and combination of immunotherapies first. Strangely, in arm C, there was no difference between the patients with high TMB and low TMB, probably because these arms are more affected by target therapy. So, we'll see in the future with more data.

Other interesting data comes from patients with JAK mutations. There was no difference among the different arms in the patients with JAK-1 type. In JAK-mutated patients, mainly in arm B, no patients progressed. So, we have 100% of patients still progression-free, 100% of patients still alive. The limitation of this analysis is the number of patients, because there are just 7 patients with JAK mutation, but the data are interesting. One possible explanation is that the JAK mutation may be related to the PD-L1 expression. So, when there is mutation, we have an increase in PDL1.

It's also important to remember, that Antoni Ribas and George Erlow, years ago, published a manuscript on New England Journal of Medicine when they found that 2 out of 4 patients who were resistant to immunotherapy had the JAK mutation. So, still interesting data, controversial, small number of patients. We'll see with more patients when we analyze the same from the other patients.

And also, the interferon gamma cytokine, not the signature, the cytokine that we evaluate in serum, showed interesting results. Not in arm A and B with a different sequence, but in arm C with the sandwich sequence. The patients with the low expression of interferon gamma cytokine serum did better. This is strange because there is a correlation with interferon gamma signatures and better outcomes. Of course, this may be the effect of the small number of patients, that needs to be confirmed but it's an interesting data.

So, in summary, what we've seen from this update of SECOMBIT trial, is that it was confirmed that the patients who were enrolled in arms where immunotherapy was given first did better in terms of, both, total progression-free survival and overall survival. Preliminary biomarker data show an interesting correlation with the tumor mutation burden, JAK mutation, and interferon cytokine with outcomes.

So, of course we need more data for the biomarker. We are evaluating more samples. We're also waiting for other analyses like gene profiling and evaluation of the tumor microenvironment of the different monosystem cell. And we are still of course collecting data for the long-term overall survival and in the next upcoming meeting, we will report also this data.

Source:

Ascierto PA, Mandalà M, Ferrucci PF, et al. Phase II study SECOMBIT (sequential combo immune and target therapy study): 4-years OS data and preliminary biomarkers evaluation. Annals Oncol. 2022;33:S1408-S1409. doi:10.1016/j.annonc.2022.08.040