Starting With Immunotherapy is More Effective in BRAF Mutation-Positive Melanoma

In advanced BRAF mutation-positive melanoma, starting treatment with an immunotherapy combination resulted in better overall survival, as shown in the phase-III DREAMseq clinical trial.

In this study, starting with nivolumab plus ipilimumab dual immunotherapy, rather than the two BRAF/MEK-targeted drugs dabrafenib plus trametinib, resulted in an absolute improvement in 2-year overall survival of 20% (p = 0.0095).

These results prompted early termination of the trial because of the clear difference in benefit in the dual immunotherapy arm.

DREAMseq's results answer one of the most important clinical questions in melanoma treatment.

What is a BRAF Mutation?

The BRAF gene encodes a protein with serine/threonine kinase activity in the mitogen-activated protein kinase intracellular signaling pathway (MAPKs). It controls cell division by acting through Kras. In malignant melanoma skin cancer, colorectal cancer and papillary thyroid cancer, somatic BRAF gene mutations  are detected. V600E is the most common mutation observed in patients.

Results of the DREAMseq Study

At year 2 of treatment:

• Overall survival was 72% among those who started with nivolumab + ipilimumab,
• compared with 52% among those who started with the BRAF inhibitors dabrafenib + trametinib.

The study therefore found that immunotherapy leads to longer-lasting treatment responses when given first line.

What is the Optimal Sequence? An Unanswered Question

Of all patients with metastatic melanoma, approximately half  have BRAF V600 mutations. Both BRAF/MEK inhibitors and nivolumab/ipilimumab have contributed to survival in this population in different ways.

Details of the DREAMseq Study

DREAMseq  enrolled previously untreated  BRAF V600-mutant metastatic melanoma patients: 265 of 300 patients (mean age, 61 years; 63% male). Patients were randomized to first-line nivolumab/ipilimumab immunotherapy (arm A) or dabrafenib/trametinib targeted therapy (arm B).

Patients in arm A received 12 weeks of induction combination immunotherapy followed by up to 72 weeks of nivolumab monotherapy. Arm B received dabrafenib/trametinib continuously.

Patients with disease progression entered step 2, involving the alternative combination. Arm A switched to dabrafenib/trametinib (arm C), and arm B to nivolumab/ipilimumab (arm D). The primary endpoint was 2-year overall survival.

Response Rates

Initial overall response rates were 46% with nivolumab/ipilimumab and 43% with dabrafenib/trametinib.

At analysis, 88% of initial immunotherapy responders and 49% in the BRAF-targeted group remained responsive. Median response duration had not yet been reached in the immunotherapy group, compared with 12.7 months in the other arm (P < 0.001).

After progression, second-line response rates were 48% with dabrafenib/trametinib and 30% with nivolumab/ipilimumab.

Progression-Free and Overall Survival Data

The progression-free and overall survival curves crossed at 6 and 10 months, respectively (see graph below):

Although dabrafenib/trametinib initially showed better progression-free survival and overall survival than nivolumab/ipilimumab, the immunotherapy combination gained the advantage at 6 and 10 months, respectively. First-line nivolumab/ipilimumab also showed a longer response duration than dabrafenib/trametinib given first (not reached versus 12.7 months; P < 0.001).

Although first-line immunotherapy response was 46%, similar to targeted therapy, the response to second-line immunotherapy after prior targeted therapy fell to 30%. This may suggest that resistance to targeted therapy can be immunosuppressive.

Regarding overall survival, of 100 deaths in the trial, 38 occurred in patients who started with nivolumab/ipilimumab and 62 in those starting targeted therapy, producing a 20% difference in survival by year 2 (P = 0.0095).

The comment was that 2-year overall survival was better with nivolumab/ipilimumab first across all subgroups.

The study closed because of these substantial differences, and patients receiving first-line dabrafenib/trametinib were offered a switch to nivolumab/ipilimumab without waiting for progression.

A total of 24 patients died less than 10 months after nivolumab/ipilimumab. They tended to have a worse disease course and/or more side effects and received "limited treatment" after progression that did not include dabrafenib or trametinib.

Notably, even in the group predicted to perform best with dabrafenib/trametinib—good performance status, normal lactate dehydrogenase and better disease stage—starting nivolumab/ipilimumab showed a strong trend toward better 2-year overall survival (P = 0.054).

Side Effects

Grade ≥ 3 toxicity (serious side effects) was higher with first-line immunotherapy: 60% versus 52%. Three treatment-related deaths occurred among patients starting immunotherapy: two during nivolumab/ipilimumab and one after switching to the targeted combination.