Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.

BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy. METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival. RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).

CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1.

The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1-PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses.

Biomarker-Driven Personalization of Neoadjuvant Immunotherapy in Melanoma.

The introduction of immunotherapy has ushered in a new era of anticancer therapy for many cancer types including melanoma. Given the increasing development of novel compounds and combinations and the investigation in earlier disease stages, the need grows for biomarker-based treatment personalization. Stage III melanoma is one of the front-runners in the neoadjuvant immunotherapy field, facilitating quick biomarker identification by its immunogenic capacity, homogeneous patient population, and reliable efficacy readout. In this review, we discuss potential biomarkers for response prediction to neoadjuvant immunotherapy, and how the neoadjuvant melanoma platform could pave the way for biomarker identification in other tumor types. SIGNIFICANCE: In accordance with the increasing rate of therapy development, the need for biomarker-driven personalized treatments grows. The current landscape of neoadjuvant treatment and biomarker development in stage III melanoma can function as a poster child for these personalized treatments in other tumors, assisting in the development of new biomarker-based neoadjuvant trials. This will contribute to personalized benefit-risk predictions to identify the most beneficial treatment for each patient.

Learning from the implementation of clinical empathy training: an explorative qualitative study in search of the barriers and facilitators.

BACKGROUND: Amid concerns about the decline of empathy during the clinical training of medical clerks, evidence that empathy improves patient outcomes suggests some potential for teaching empathy in ways that will affect the knowledge, attitude and behaviour of medical clerks. This potential alone cannot, however, guarantee the success of educational innovations to introduce empathy to the medical curriculum. This research aims to identify the barriers and facilitators of the implementation of a specific clinical initiative to enhance the empathy skills of clerks, namely the training of clerks to act as a 'MedGezel' or 'medical coach'. METHOD: We conducted an explorative qualitative study based on interview data collected and analyzed using reflexive thematic analysis and the readiness for change theory. We conducted semi-structured interviews with relevant stakeholders in this particular qualitative study. Thematic analysis was based on open and axial coding using ATLAS.ti 9, which facilitated the emergence of common themes of interest and meaning for the study. RESULTS: A total of 13 relevant stakeholders participated as interviewees in our study. The data was collected from April to June 2021. Our analysis generated 6 main themes which can provide insights into why the implementation of the MedGezel educational innovation failed so far. The following themes emerged: the case for change: why change?; practical necessity; leadership; management and resources; staff culture; and alignment with the corporate strategy. DISCUSSION: The implementation failure can be partially explained as resulting from the personal attitudes and choices of participants, who struggled to reconcile a vision that they liked with side effects that they feared. While participants repeatedly mentioned management and leadership issues, these organizational issues seemed less important as they could be easily resolved in practice. What was more important and fatal for the initiative was its lack of alignment with staff culture, despite its alignment with corporate strategy. CONCLUSION: This investigation into the barriers and facilitators influencing the implementation of the MedGezel program identified 6 explanatory themes, the most impactful one being staff culture.