Selected Articles from This Issue

The standard of care for locally advanced rectal cancer treatment is surgical excision combined with 5-FU-based chemoradiation. Although preclinical studies have identified many agents with potential synergy with 5-FU chemoradiation, none have shown a clinical benefit. Wu and colleagues performed a phase I trial to assess the safety of combining trametinib, a potent and selective MEK1/2 inhibitor, with 5-FU chemoradiation in patients with locally advanced rectal cancer. This combination was well tolerated, and at the highest trametinib dose, 25% of patients showed a pathological complete response. A phase II study is necessary to determine the efficacy of this combination in patients with rectal tumors that harbor KRAS, NRAS, and BRAF mutations.

Preclinical studies have suggested that androgen deprivation therap. (ADT) can promote antitumor immunity in prostate cancer. Obradovic and colleagues conducted a randomized clinical trial in which men with localized prostate cancer were treated prior to surgery with either ADT alone or the combination of a cancer vaccine (GVAX) plus ADT. In both groups, ADT induced a complex immune infiltrate with an approximate two-fold increase in CD8+ cells, balanced by a proportional increase in Tregs. This effect, “adaptive Treg resistance,” may explain why strategies aimed at increasing CD8+ cell activity lack efficacy in prostate cancer. Though the addition of GVAX did not increase T-cell infiltration versus ADT alone, vaccine treatment was associated with an increase in time-to-PSA-recurrence, suggesting that it may have effects beyond increasing CD8+ T-cell infiltration.

While crizotinib is initially effective for patients with ROS1⁺ lung cancer, recurrence is common, including involvement with the central nervous system. Yun and colleagues assessed repotrectinib, a novel next-generation ROS1-TKI, in a ROS1⁺ patient-derived lung cancer model with crizotinib resistance. Repotrectinib demonstrated efficacy both in vitro and in vivo. Furthermore, repotrectinib crossed the blood-brain barrier and inhibited growth of intracranial xenografts of this patient-derived model. These results were confirmed by clinical responses in ROS1⁺ patients with treatment-naïve disease and crizotinib-resistant G2032R mutations. Therefore, repotrectinib could serve as an effective first-line treatment in ROS1⁺ NSCLC, including those with G2032R mutations.

Although melanoma is considered a relatively immunoresponsive tumor type, improved biomarkers for immunotherapy outcome remain elusive in this disease setting. As part of a clinical trial of the hu14.18-IL2 immunocytokine in melanoma, Yang and colleagues performed whole-transcriptome sequencing of tumors to identify tumor and immune biomarkers of response. In patients receiving hu14.18-IL2 before surgical resection, levels of tumor infiltrating lymphocytes correlated with RFS and OS. Furthermore, increased expression of genes related to cytotoxic T cells, NK cells, and innate immune cells correlated with improved survival. Differences in melanoma markers, glycolysis components, and DNA repair factors were observed and compared with untreated tumors. Thus, prognostic information can be derived from RNA-seq data and may facilitate patient management.