Presurgical Targeted Therapy, Immunotherapy Show Responses in Melanoma

Presurgical treatment with targeted therapy and immunotherapy resulted in notable responses among some patients with high-risk resectable (removable by surgery) stage 3 melanoma, researchers have found.

Researchers for the phase 2 NeoACTIVATE trial, who published their findings in Nature Communications, reported that 15 patients each were treated with neoadjuvant (presurgical) Zelboraf (vemurafenib), Cotellic (cobimetinib) and Tecentriq (atezolizumab) if their disease was BRAF-mutated. Patients whose disease was BRAF-wild-type (meaning there is no BRAF mutation) were treated with Cotellic and Tecentriq. The therapies were followed by therapeutic lymph node dissection (surgical removal of the lymph nodes) and 24 weeks of adjuvant (postsurgical) Tecentriq.

“The last 13 years or so have been really exciting in the field of melanoma in that a number of different new treatments have been developed,” said Dr. Matthew Block, leader of the Stand Up to Cancer Catalyst Research Team that ran the study. Block is also an immunologist and medical oncologist at the Mayo Clinic Comprehensive Cancer Center and senior author of the study, which he discussed in an interview with CURE®.

“Broadly speaking, most of these can be classified as either targeted treatments — treatments that inhibit a protein and inhibit some of the functions of melanoma [such as] the tendency to divide, the tendency to survive when cells should die, the target protein therapies can disrupt that — and the immunotherapies are another category of treatment and they disrupt the cancer's ability to evade the immune response,” said Block. “So, we have two effective approaches. This trial has combined those in patients who have a resectable melanoma that is at very high risk for recurrence.

“The other novelty of this clinical trial [is that] at the time that it was designed [in 2017], most of the time, we were using these drug therapies after an operation. But in this trial, we sought to use the drug treatments prior to the operation, thinking that they might work better with the tumor in place rather than waiting until it had been cut out.”

LEARN MORE: Some Researchers Urge Caution of Immunotherapy in Older Patients with Melanoma

Among patients with BRAF-mutated disease, 86.7% experienced a pathologic response (a reduction in cancer cells), with 66.7% experiencing a major pathologic response (10% or fewer cancer cells found in their lymph nodes during surgery). For patients with BRAF-wide-type disease, those numbers were 53.3% and 33.3% of patients, respectively.

“When we took the disease out and gave the tissue to the pathologist to look at under the microscope, we could see that the majority of the tumor was gone in a high proportion of patients, and over half of the patients had a very major pathologic response, which we define as having no identifiable tumor cells or just a few, less than 10%,” said Dr. Tina J. Hieken, clinical lead for the Research Team, surgical oncologist at Mayo Clinic Comprehensive Cancer Center and first author of the study, in an interview with CURE®.

“We also found that this approach was associated with good post-operative outcomes,” Hieken added. “That means that we didn't jeopardize the safety of surgery by giving these treatments before surgery, our complication rate [with eight of 28 patients who underwent surgery experiencing complications] was favorable compared to doing the operation first. And then very importantly, particularly the time when the study started, we did not identify that any patient had progression that prevented them from having a curable operation.”

“In 2017, the standard of care had been to first do the operation and then give the drug treatment afterward,” said Block. “But due to this study, and due to a number of other studies that have been conducted in parallel, the paradigm is shifting. And now the standard of care is [moving] towards giving neoadjuvant or preoperative drug treatment like was done in our study. And so, although the [Food and Drug Administration (FDA)] has not yet approved preoperative or neoadjuvant treatment, that is clearly becoming the shift at most institutions.”

Researchers reported that 63% of patients experienced at least one grade 3 (severe) side effect, with a 53% rate of grade 3 skin-related side effects among patients with BRAF-mutated disease.

The trial has an additional third arm that is currently recruiting and will give two types of immunotherapy drugs to patients in order to see if the trial’s pathologic response rates and survival outcomes can be recreated with fewer side effects, Hieken said.

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