MELANOMA

Adjuvant therapy for stage III melanoma without immediate completion lymph node dissection

A recent study suggests that modern adjuvant therapy in patients who forego completion lymph node dissection (CLND) is associated with longer distant metastasis-free survival (DMFS) among patients with Stage IIIb/c melanoma (Ann Surg Oncol 2022;29:806-15). For patients with Stage III melanoma with occult lymph node metastasis, the use of CLND has decreased in recent years, while adjuvant therapy continues to increase. And so, a team of researchers sought to better understand the outcomes among patients who did not undergo surgery. This retrospective study included 90 patients who a positive sentinel lymph node biopsy and did not have CLND. The study authors evaluated nodal recurrence, recurrence-free survival (RFS), DMFS, and melanoma-specific survival. Of the included patients, 56 (62%) received adjuvant therapy while 34 (38%) underwent observation alone. Data showed that patients who received immunotherapy had better rates of DMFS. Disease recurrence occurred in 12 of 34 patients (35%) in the observation group and 11 of 56 (20%) in the adjuvant therapy group, according to the study authors. They reported that the most common first site of recurrence was distant recurrence alone in the observation group and nodal recurrence alone among those who received adjuvant therapy. The study authors also found that-in spite of more adverse nodal features in the adjuvant therapy group-24-month nodal recurrence rate and RFS were not significantly different between the two groups. However, adjuvant therapy was associated with a significantly improved 24-month DMFS (86% vs. 59%) among patients with Stage IIIb/c disease.

AUTHOR COMMENTARY: The researchers hope the study will lead to a shift in practice for this patient population, according to Martin McCarter, MD, Professor of Surgical Oncology at the University of Colorado School of Medicine. "Previous clinical trials with the use of adjuvant immunotherapy for melanoma had required a CLND. This study used real-world data from our Stage III melanoma patients who were treated with immunotherapy without having a prior CLND," he noted in a statement. "It takes years to change people's practice patterns. I still have conversations with community surgeons who treat melanoma, asking me, 'Should I be doing these regional node dissections?' even though this data has been out for 5-10 years now. They're afraid to give up what they used to do, and they're afraid that they are doing a disservice to the patients or not giving them the best chance, when in reality, our understanding of cancer biology has evolved. We now have effective immunotherapy, which is overcoming some of the limitations of surgery while improving outcomes."

OVARIAN CANCER

Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial

Findings revealed that the MEK inhibitor trametinib offers a new standard-of-care option for patients with recurrent low-grade serous ovarian carcinoma (Lancet 2022;399(10324):541-53). In this international, randomized, open-label, multicenter, Phase II/III trial, the MEK inhibitor trametinib was compared to physician's choice standard of care in patients with recurrent low-grade serous carcinoma. Eligible patients were 18 years or older; had underwent at least one platinum-based regimen, but not all five standard-of-care drugs; and had received an unlimited number of previous regimens. They were randomly assigned 1:1 to receive either oral trametinib 2 mg once daily (n=130) or one of five standard-of-care treatment options (n=130). The primary endpoint of the study was investigator-assessed progression-free survival while receiving randomized therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. The researchers assessed safety in patients who received at least one dose of study therapy. At the primary analysis, the researchers reported 217 progression-free survival events: 101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group. Data showed a median progression-free survival of 13 months among patients who received trametinib compared with 7.2 months in the standard-of-care group. The most frequent Grade 3 or 4 adverse events in the trametinib group were skin rash, anemia, hypertension, diarrhea, nausea, and fatigue. Comparatively, the most frequent Grade 3 or 4 adverse events in the standard-of-care group were abdominal pain, nausea, anemia, and vomiting. The researchers reported no treatment-related deaths.

AUTHOR COMMENTARY: "Our trial is the first positive randomized trial of any therapy in low-grade serous carcinoma showing that the MEK inhibitor trametinib reduced the risk of disease progression or death by 52 percent compared with investigator's choice of endocrine therapy or chemotherapy," the study authors concluded. "Trametinib was also associated with a four-fold increase in the probability of response to therapy, and showed a trend toward an overall survival benefit, despite the 68 percent of patients in the standard-of care group who crossed over to trametinib."

ENZYME INHIBITORS

EZH2 noncanonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis

Researchers recently identified a new role of a chromatin-modulatory enzyme, EZH2, during cancer development. Following this discovery, the team then developed a new therapeutic approach with a potent small-molecule inhibitor of this enzyme, MS177. This was designed based on proteolysis-targeting chimera (PROTAC) technology and targets both EZH2 and cMyc, which results in the inhibition of cancer growth. "Here, we report that in acute leukemias, EZH2 has additional noncanonical functions by binding cMyc at non-PRC2 targets and uses a hidden transactivation domain (TAD) for (co)activator recruitment and gene activation," the study authors explained. "Both canonical (EZH2-PRC2) and noncanonical (EZH2-TAD-cMyc-coactivators) activities of EZH2 promote oncogenesis, which explains the slow and ineffective anti-tumor effect of inhibitors of the catalytic function of EZH2." They also reported that MS177 achieves on-target effect in cancer cells and exhibits profound tumor killing effects. Compared with other inhibitors, the researchers noted that MS177 is fast-acting and more potent in suppressing cancer growth, offering an effective strategy for the treatment for EZH2-dependent cancers.

AUTHOR COMMENTARY: "Compared to the existing enzymatic inhibitors, MS177 is more likely to behave much better for the treatment of patients with acute leukemias. To our knowledge, an agent for dual targeting of EZH2 and cMyc has not been developed before. cMyc is hard to 'drug,'" said Greg Wang, PhD, Associate Professor of Biochemistry and Biophysics and Pharmacology at the UNC School of Medicine and co-lead author of this research. "MS177 thus represents a promising candidate for treating other cancers depending on the above tumorigenic pathways."