ORR Raised to 85% With Neoadjuvant, Adjuvant Dabrafenib/Trametinib Combo

Jennifer Wargo, MD, MMSc

Neoadjuvant and adjuvant dabrafenib (Tafinlar) plus trametinib (Mekinist) increased the overall response rate (ORR) to 85% in patients with high-risk resectableBRAF-mutant metastatic melanoma. And interestingly, the pathologic complete response (pCR) rate with the combination was 58%, as demonstrated in findings presented during the 2017 ASCO Annual Meeting.

A team led by Rodabe Amaria, MD, Assistant Professor, Department of Melanoma Medical Oncology, and Jennifer Wargo, MD, MMSc, Associate Professor, Department of Surgical Oncology and Department of Genomic Medicine, bboth of The University of Texas MD Anderson Cancer Center conducted a prospective single institution randomized clinical trial inBRAF-mutant patients with resectable stage IIIb/stage IIIc or oligometastatic melanoma. They also found that patients with a pCR at surgery had significantly improved relapse-free survival (RFS) rates versus patients without pCR on neoadjuvant dabrafenib plus trametinib (P= .04).

“Standard of care surgery for high-risk bulky melanoma, with or without adjuvant therapy, is associated with a high risk of relapse, so we wanted to explore whether the same agents that have dramatically improved outcomes in stage IV melanoma patients would work in earlier stage disease,” said Wargo in an interview withTargeted Oncology. “These RFS data are promising. Additionally, pCR may be prognostic for long-term benefits to the patient as well.”

Patients were randomized 1:2 to standard of care versus neoadjuvant and adjuvant dabrafenib plus trametinib. The experimental group received 8 weeks of neoadjuvant therapy before restaging and surgical resection followed by up to 44 weeks of adjuvant therapy. The control group received interferon, high-dose ipilimumab (Yervoy), biochemotherapy, or observation alone following surgical resection.

RFS was the primary endpoint. Tumor biopsies were collected at baseline, week 3, and at surgery for molecular and immune profiling. This consisted of whole exome sequencing, gene expression profiling, immunohistochemistry (IHC) and flow cytometry. Patients in both groups received physical examinations and imaging every 12 weeks after surgery for at least 2 years to assess for disease recurrence.

The investigators enrolled 21 of a planned 84 patients, with 7 in the control group and 14 in the experimental group. &ldquo;The trial arms were well balanced for standard prognostic factors and toxicity was manageable,&rdquo; Amaria noted. The first interim analysis revealed significantly improved RFS in the experimental arm (hazard ratio [HR], 62.5;P<.0001), which led to enrollment being closed early.

In comparing clinical and pathological responses, the investigators found little variation in the probable OS rates between the control and experimental groups (HR, 0.29; 95% CI, 0.026-2.24). However, both the RFS and distant metastasis-free survival (DMFS) probabilities showed dramatic differences between the 2 groups. The RFS HR was 0.016 (95% CI, 0.00012-0.14;P<.0001). The DMFS HR was 0.025 (95% CI, 0.00018-0.29;P= .002).

Tumor profiling revealed incomplete MAPK pathway blockade and higher levels of CD8-positive T cells expressing the immunomodulators Tim-3 and Lag-3 in patients who did not achieve a pCR. The investigators also found that pCR in patients treated with neoadjuvant dabrafenib plus trametinib is associated with changes in T-cell phenotype and repertoire.

For example, the tumors before treatment in patients who went on to achieve pCR showed a relative abundance of CD8-positive cells compared with tumors in patients who did not experience pCR. Additionally, in 5 of the 7 patients who achieved a pCR, the 5 most dominant T-cell clones comprised more than 5% of the total T-cell repertoire based on the pathological response status. This was not true of any patient who experienced either a pathologic partial response or non-response.

Global analysis did not identify any specific gene mutation or copy number variation patterns to associate with clinical outcomes. The presence of well-established melanoma-associated somatic gene aberrations was frequently identified in non-pCR versus pCR outcome tumors.

Transcriptional profiling found that tumors from pCR patients revealed relatively dynamic increases while those from patients who did not achieve a complete response showed relatively static expression. &ldquo;Those with a pCR essentially went from a cold tumor to a hot tumor. The tumors in patients without a complete response remained quiescent,&rdquo; Wargo noted.

In light of this trial&rsquo;s high response rates, Amaria says further study is warranted: &ldquo;Studying this in the context of clinical trials with critical correlative studies is key, and several such trials are already underway.&rdquo;

In the future, Wargo would like to continue the molecular and immune phenotyping of responders versus nonresponders, including whole exome sequencing, proteomics, TCR sequencing, reverse phase protein arrays, and circulating BRAF and other biomarkers. Additionally, the analysis of the ongoing randomized phase II clinical trial (Combi-Neo) is promising.

&ldquo;Ultimately, this could change the standard of care for this challenging patient population, but we are not there yet,&rdquo; she said.

Reference:

Wargo J, Amaria R, Prieto P, et al. Relapse-free survival and target identification to enhance response with neoadjuvant and adjuvant dabrafenib + trametinib (D+T) treatment compared to standard-of-care (SOC) surgery in patients (pts) with high-risk resectable BRAF-mutated metastatic melanoma.J Clin Oncol35, 2017 (suppl; abstr 9587).