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We previously demonstrated that patients with metastatic unresectable stage IIIb–IV melanoma receiving cetirizine (a second-generation H1 antagonist antihistamine) premedication with immunotherapy had better outcomes than those not receiving cetirizine. In this retrospective study, we searched for a gene signature potentially predictive of the response to the addition of cetirizine to checkpoint inhibition (nivolumab or pembrolizumab with or without previous ipilimumab). Transcriptomic analysis showed that inducible T cell costimulator ligand (ICOSLG) expression directly correlated with the disease control rate (DCR) when detected with a loading value > 0.3. A multivariable logistic regression model showed a positive association between the DCR and ICOSLG expression for progression-free survival and overall survival. ICOSLG expression was associated with CD64, a specific marker of M1 macrophages, at baseline in the patient samples who received cetirizine concomitantly with checkpoint inhibitors, but this association was not present in subjects who had not received cetirizine. In conclusion, our results show that the clinical advantage of concomitant treatment with cetirizine during checkpoint inhibition in patients with malignant melanoma is associated with high ICOSLG expression, which could predict the response to immune checkpoint inhibitor blockade. [ABSTRACT FROM AUTHOR]

Introduction In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need. Materials and Methods We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P  < .05) and Bayesian statistics (BF10). Results Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N  = 43, 63%), without Gorlin syndrome (N  = 56, 82%) and with head and neck area as primary site (N  = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N  = 50/61) due to toxicity (R1), and 18% (N  = 11/61) due to recurrence (R2). Conversely, 10% (N  = 7/68) continued vismodegib until last follow-up. In the whole population (N  = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P  < .01, BF10 = 39.2) and TTD (P  < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N  = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N  = 38, r  = 0.44, P  < .01) and in the recurrent patients who stopped vismodegib for toxicity (N  = 26, r  = 0.665, P  < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N  = 54 vs. ≤ 2 months, N  = 14: 470 vs. 175 d, P  < .01). Conclusions Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC. [ABSTRACT FROM AUTHOR]

Background: The impact of the order of treatment with checkpoint inhibitors or BRAF/MEK inhibitors on the development of brain metastases in patients with metastatic unresectable BRAF V600-mutant melanoma is unknown. The SECOMBIT trial examined the impact of the order of receipt of these treatments in such patients., Methods: In this three-arm trial, we reviewed patients without brain metastases who received the BRAF/MEK inhibitors encorafenib and binimetinib until they had progressive disease followed by the immune checkpoint inhibitors ipilimumab and nivolumab (arm A); or treatment with ipilimumab and nivolumab until they had progressive disease followed by encorafenib and binimetinib (arm B); or treatment with encorafenib and binimetinib for 8 weeks followed by ipilimumab and nivolumab until they had progressive disease followed by retreatment with encorafenib arm binimetinib (arm C)., Results: Brain metastases were discovered during the trial in 23/69 patients in arm A, 11/69 in arm B, and 9/68 in arm C. At a median follow-up of 56 months, the 60-month brain metastases-free survival rates were 56% for arm A, 80% for arm B (hazard ratio [HR] vs. A: 0.40, 95% confidence interval [CI] 0.23 to 0.58), and 85% for arm C (HR vs. A: 0.35, 95% CI 0.16 to 0.76)., Conclusions: In patients with unresectable metastatic melanoma, the treatment sequence of immune checkpoint inhibition followed by BRAF/MEK inhibitors was associated with longer periods of new brain metastases-free survival than the reverse sequence. A regimen in which immune checkpoint inhibition was sandwiched between BRAF/MEK inhibition also appeared to be protective against brain metastases. (ClinicalTrials.gov number NCT02631447.).