Presurgical Targeted Therapy Delays Relapse of High-Risk Stage III Melanoma

Key Points

  • All seven patients treated with standard of care surgery had their disease progress, with median time to progression at 2.9 months.
  • Of 14 patients randomized to the neoadjuvant combination, 4 progressed, with median time to progression of 19.7 months.
  • Of the seven patients who achieved a pathologic complete response after presurgical therapy, none experienced distant disease relapse.

A pair of targeted therapies given before and after surgery for melanoma produced at least a sixfold increase in time to progression compared to standard-of-care surgery for patients with stage III disease, Amaria et al reported in The Lancet Oncology. Patients who had no sign of disease at surgery after combination treatment did not progress to metastasis.

Early results of the study comparing surgery to pre- and post-surgical treatment with the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor (Mekinist) trametinib were so strikingly positive that MD Anderson’s data safety monitoring board ordered the randomized, prospective phase II trial halted and changed to a single-arm using the combination.

“These results are encouraging for patients with surgically resectable stage III melanoma, who face a high rate of relapse and progression to metastatic disease,” said lead author Rodabe Amaria, MD, Assistant Professor of Melanoma Medical Oncology at MD Anderson. “Our proof-of-concept study strongly supports further assessment of neoadjuvant therapy for this high-risk population, which has a 5-year survival rate of less than 50%.”

The targeted combination is approved by the U.S. Food and Drug Administration for stage IV metastatic melanoma that features a BRAF V600 mutation. Dr. Amaria, senior author Jennifer Wargo, MD, Associate Professor of Surgical Oncology and Genomic Medicine, and colleagues hypothesized that the combination could help patients with stage III BRAF-mutant disease.

Trial Findings

The trial was designed to enroll 84 patients randomized to either upfront surgery or to 8 weeks of the targeted combination followed by surgery and another 44 weeks of combination treatment. An interim data analysis occurred after 21 patients were treated. 

At a median follow-up time of 18.6 months:

  • All seven patients treated with standard of care surgery had their disease progress, with median time to progression at 2.9 months.
  • Of 14 randomized to the neoadjuvant combination, 4 progressed, with median time to progression of 19.7 months.
  • Of the 7 patients who achieved a pathologic complete response after presurgical therapy, none experienced distant disease relapse.
  • Median overall survival had not been reached in either arm.

Importance of Pathologic Complete Response

Reaching pathologic complete response appears to be a powerful indicator of treatment success, Dr. Amaria said. Twelve patients in the neoadjuvant group proceeded to surgery, with seven achieving pathologic complete response. Only one relapsed, with a small tumor in the same area as the original tumor. Three patients who reached a partial pathologic response relapsed, with all developing brain metastases, a common risk in BRAF-positive disease.

“As we accumulate more data, we can further explore the importance of pathologic complete response,” Dr. Wargo said. “If we can prove that pathologic complete response is important in achieving superior outcomes, then the next step is to ask ‘what can you do to get to [pathologic complete response]?’”

Biopsies and blood samples taken in the trial allowed the team to begin to address those issues.

  • Patients that did not reach pathologic complete response had tumors with high levels of phosphorylated ERK, a growth-promoting protein in the MEK pathway, before combination treatment began.
  • Research has shown evidence of an immune response in successful treatment with BRAF inhibitors, even though these drugs are not explicitly immunotherapies. The team found penetration of tumors by CD8-positive T cells in pathologic complete response patients, but evidence of T-cell exhaustion in tumors of patients who did not reach pathologic complete response. Two checkpoint proteins that stifle immune response, TIM3 and LAG3, were found in abundance on T cells in those patients.
  • Whole-exome sequencing revealed no significant difference in mutational load or copy-number alterations at baseline between responders and nonresponders. However, those who did not reach pathologic complete response often had known genetic aberrations that cause resistance to the combination.

These differences provide pathways for larger, additional studies and point to possible combination therapy approaches. Since the original trial was halted, 11 patients have enrolled in the neoadjuvant study.

Toxicities from the combination were primarily grade 1 and 2 side effects expected with dabrafenib and trametinib, most commonly chills, headache, and fever. There were eight grade 3 events, no grade 4 events, and no deaths related to treatment. Two patients in the surgical arm and one in the neoadjuvant arm died from disease progression.

Those in the standard-of-care surgery arm were offered a variety of adjuvant therapies, including interferon-alpha, the checkpoint blockade drug ipilimumab (Yervoy), biochemotherapy, or observation. Existing adjuvant therapies at the time the trial was enrolling had extremely low response rates as well as harsh side effects, Dr. Amaria said. Only one patient chose to have postsurgical therapy in that arm.

Novartis Pharmaceuticals provided drugs and funded the clinical aspects of the study, but played no role in study design, execution, data collection, analysis, or interpretation. Correlative studies of tumors and blood samples were funded by the Cancer Prevention and Research Institute of Texas, MD Anderson’s Melanoma Moon Shot, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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