A pair of target treatments conducted before and after the operation for melanoma , has caused, at least a six-fold increase in the time to relapse as compared with standard surgery for patients with melanoma third step. Patients who had no signs of disease during the operation after the combined treatment not progressed to metastases.
Early results of a study comparing surgery with pre- and post-operative treatment of melanoma with BRAF dabrafenib inhibitor and an inhibitor of MEK trametinib, were so strikingly positive that had a new randomized trial.
"These results are encouraging for patients with surgically rezektiruemoy third stage melanoma who are faced with a high rate of recurrence and progression to metastatic disease," - said the lead author Rodabe Amariah, MD, associate professor of medical oncology melanoma. "Our study of the concept of evidence strongly supports further evaluation of neoadjuvant therapy for this group of high risk, which has a five-year survival rate of less than 50 percent."
The target combination is approved for the control of the US Food and Drug Administration for the treatment of metastatic melanoma stage 4 , which has a mutation BRAFV600. The researchers suggested that this combined treatment can help patients and a third stage of the disease with a mutation of the BRAF.
The trial version, which was launched with the help of Moon Shots program.
In October 2014 the investigator-initiated clinical trial was initiated to accelerate the improvement of the treatment and prevention of cancer. This was the first prospective randomized neoadjuvant clinical trial for melanoma stage 3.
Its essence is to register the 84 patients randomized to perform the first operation, or up to eight weeks, followed by a combination of focused and surgery another 44 weeks of combination therapy. Interim analysis occurred after treating 21 patients.
With a median observation time of 18.6 months:
All seven patients who received standard therapy were disease progression, the median time to progression - 2.9 months. Of the 14 randomized to combination neoadjuvant four progressed, with an average time to progression of 19.7 months.
Of the seven patients who were pathological complete response after preoperative therapy, no one has observed a distant disease recurrence. The median overall survival has not been reached in any of the groups.
Most melanoma is detected early and successfully treated by surgery, but about 15 percent of patients advance to the third stage, when the disease has spread to the lymph nodes.
The importance of pathological complete response
According to Amari, achieving complete pathological response (pCR) - no evidence of the existence of cancer discovered during surgery - is a powerful indicator of treatment success. Twelve patients in the neoadjuvant group started operations seven achievements pCR. Only one relapse, with a small tumor in the same area, where the first was located. Three patients who achieved pathologic partial response recurred with all developing brain metastases, overall risk in BRAF-positive disease.
"With the accumulation of more data we can further explore the importance of pathological complete response" - Uorgo said. "If we can prove that the pathologic complete response is important in order to achieve excellent results, the next step is to ask" what can you do to achieve a pCR? ».
Biopsy and blood samples taken during the study allowed the team to begin to solve these problems.
Patients who have not achieved the pCR, had tumors with high levels of ERK phosphorylation, stimulates protein MEK growth path before the combined treatment.
Studies have shown evidence of immune response in the successful treatment of the BRAF inhibitors, although these drugs are not explicitly immunotherapy. The team found the penetration of tumor CD8-positive T-cells in pCR patients, but evidence of the depletion of T cells in the tumors of patients who did not achieve pCR. Two checkpoint protein that prevented an immune response, TIM3 and LAG3, were found in abundance on T cells in these patients.
The whole sequence of sequencing revealed no significant differences in changes in mutational load or the number of copies at baseline between respondents and non-responders. However, those who have not reached the AUC, often known genetic aberrations that cause resistance to the combination.
These differences provide a way for larger and additional studies point to possible approaches to combination therapy. Since the initial study was stopped, 11 patients were enrolled in the study of neoadjuvant.
The toxicity of the combination was primarily a side effect of 1 and 2 degrees, expected at application dabrafeniba and trametiniba, often chills, headache and fever.
Those who are in surgical department, have been proposed various adjuvant (post-operative) therapies, including interferon-alpha, checkpoint block preparation ipilimumab, or biochemotherapy observation. According to Amari, the current adjuvant therapy at the time of enrollment in the study had very low response rates and dramatic side effects. Only one patient decided to conduct post-operative therapy in this group.
Target a combination of both drugs - inhibitors of the checkpoint showed prospects as an adjuvant therapy in recent clinical trials.
Researchers at MD Anderson have developed an international consortium for the development of melanoma neoadjuvant larger clinical trials necessary for further study of this approach.
Source: Lancet Oncology