乌鸦传媒

Giving targeted therapy before and after surgery for high-risk BRAF-mutant melanoma led to more than a six-fold improvement in event-free survival (EFS) compared with surgery alone, a small clinical trial showed.

Patients who received the targeted combination of dabrafenib (Tafinlar) and trametinib (Mekinist) had a median EFS of 19.7 months as compared with 2.9 months for patients who had surgery and then were considered for adjuvant therapy on a case by case basis. Enrollment in the trial ended prematurely after only 21 patients had been accrued, as a prespecified interim safety analysis showed as significant EFS benefit in favor of patients who received targeted therapy before and after surgery, reported Jennifer Wargo, MD, of MD Anderson Cancer Center in Houston, and colleagues, in .

"For patients with bulky stage III melanoma, the current standard of care is upfront surgery," Wargo told 乌鸦传媒. "But we know that up to 70% of those patients will eventually relapse and die of the disease. We hypothesized that if you treat patients before they go to surgery, that they would have better outcomes than if you took them to surgery first."

"The RECIST response rate was 85% and the pathological complete response rate was 58%, meaning they had no viable tumor at the time of surgery," she added. "The disease control rate was 100%, as none of the patients had disease progression."

The trial adds to evidence that systemic therapy before or after surgery can improve outcomes in patients with resectable stage III melanoma. Two studies reported at the 2106 European Society for Medical Oncology conference showed significant improvement in recurrence-free survival in patients who received adjuvant dabrafenib/trametinib or adjuvant nivolumab (Opdivo).

The accumulation of favorable evidence has demonstrated the feasibility of neoadjuvant and adjuvant therapy for high-risk stage III melanoma, but the optimal approach to treatment remains unclear, according to the .

Only one patient in the standard-care arm received adjuvant chemotherapy, which could reflect an imbalance in characteristics of the two treatment groups, wrote Paolo A. Ascierto, MD, of Instituto Nazionale Tumori Fondazione "G Pascale" in Naples, Italy, and Alexander M. M. Eggermont, MD, PhD, of Gustave Roussy Cancer Institute in Villejuif, France.

Moreover, three patients who received both neoadjuvant and adjuvant therapy subsequently had a first relapse in the brain, "raising the question of whether neoadjuvant plus adjuvant dabrafenib and trametinib might induce a resistant phenotype predisposed to the development of CNS metastases."

"Combining neoadjuvant therapy with adjuvant therapy can provide additional benefits, including possibly reducing the extent of surgery, making radiotherapy redundant, and increasing distant metastasis-free survival and overall survival," Ascierto and Eggermont continued. "The next generation of adjuvant trials should aim to address these outstanding questions."

The basis for the phase II randomized trial of dabrafenib/mekinist came from the agents' success in the treatment of BRAF-mutant metastatic (stage IV) melanoma. For patients with clinical stage III melanoma, the standard of care is surgical resection and consideration of adjuvant therapy. However, that approach rarely proves to be curative, Wargo's group noted.

Neoadjuvant therapy, already standard of care for many types of cancer, has played a limited role in the management of melanoma, primarily because of the disease's lack of responsiveness to conventional chemotherapy. By specifically targeting BRAF-mutant melanoma, neoadjuvant therapy with dabrafenib/trametinib offered the potential to improve on outcomes attained with upfront surgery and selective use of targeted systemic therapy.

Patients eligible for the randomized trial had BRAF-positive, surgically resectable, clinical stage III melanoma, defined as at least one palpable lymph node metastasis. Patients with oligometastatic stage IV melanoma were eligible if they had fewer than four sites of metastasis, excluding bone.

Investigators randomized patients 2:1 to receive 8 weeks of neoadjuvant dabrafenib/trametinib followed by surgery and up to 44 weeks of adjuvant dabrafenib/trametinib or to standard of care. Patients assigned to standard of care had upfront surgery and were offered standard adjuvant therapy: interferon-alfa2b, pegylated interferon-alfa2b, ipilimumab (Yervoy), a five-drug biochemotherapy regimen, or observation.

The primary endpoint was investigator-assessed EFS at 12 months. The trial ended after enrollment of one-fourth of the anticipated study population (seven patients treated with standard of care; 14 assigned to neoadjuvant/adjuvant therapy), as a prespecified interim analysis showed a significant improvement in the primary endpoint with the targeted therapy plus surgery.

After a median follow-up of 18.6 months, 10 of 14 (71%) patients assigned to dabrafenib/trametinib remained alive without disease progression as compared with none of the seven patients assigned to standard of care. The 16.8-month difference in median EFS represented almost a 99% reduction in the EFS hazard (HR 0.016, 95% CI 0.00012-0.14, P<0.0001).

Neoadjuvant/adjuvant therapy was well tolerated, including no grade 4 or fatal adverse events, the authors reported. The most common adverse events were consistent with the known toxicities of dabrafenib and trametinib, including grade 1/2 chills (92%), headache (92%), and pyrexia (77%). The most common grade 3 adverse event was diarrhea, which occurred in two (15%) patients.