Long-term follow-up of anti-PD-1 naïve patients with metastatic melanoma treated with IDO/PD-L1 targeting peptide vaccine and nivolumab

Background We have previously published initial efficacy of the indoleamine 2,3-dioxygenase (IDO)/anti-programmed death ligand 1 (PD-L1) vaccine in combination with nivolumab in 30 anti-PD-1 therapy naïve patients with metastatic melanoma (cohort A). We now report long-term follow-up of patients in cohort A. Further, we report results from cohort B, where the peptide vaccine was added to anti-PD-1 therapy for patients with progressive disease during anti-PD-1 treatment.Methods All patients were treated with a therapeutic peptide vaccine in Montanide targeting IDO and PD-L1 combined with nivolumab (NCT03047928). A long-term follow-up of safety, response rates, and survival rates were performed in cohort A including patient subgroup analyses. Safety and clinical responses were analyzed for cohort B.Results Cohort A: At data cut-off, January 5, 2023, the overall response rate (ORR) was 80%, and 50% of the 30 patients obtained a complete response (CR). The median progression-free survival (mPFS) was 25.5 months (95% CI 8.8 to 39), and median overall survival (mOS) was not reached (NR) (95% CI 36.4 to NR). The minimum follow-up time was 29.8 months, and the median follow-up was 45.3 months (IQR 34.8–59.2). A subgroup evaluation further revealed that cohort A patients with unfavorable baseline characteristics, including either PD-L1 negative tumors (n=13), elevated lactate dehydrogenase (LDH) levels (n=11), or M1c (n=17) obtained both favorable response rates and durable responses. The ORR was 61.5%, 79%, and 88% for patients with PD-L1− tumors, elevated LDH, and M1c, respectively. The mPFS was 7.1 months for patients with PD-L1− tumors, 30.9 months for patients with elevated LDH, and 27.9 months for M1c patients. Cohort B: At data cut-off, the best overall response was stable disease for 2 of the 10 evaluable patients. The mPFS was 2.4 months (95% CI 1.38 to 2.52), and the mOS was 16.7 months (95% CI 4.13 to NR).Conclusion This long-term follow-up confirms the promising and durable responses in cohort A. Subgroup analyses of patients with unfavorable baseline characteristics revealed that high response rates and survival rates were also found in patients with either PD-L1 negative tumors, elevated LDH levels, or M1c. No meaningful clinical effect was demonstrated in cohort B patients.Trial registration number NCT03047928

Vaccination against pd-l1 with io103 a novel immune modulatory vaccine in basal cell carcinoma:A phase iia study

Antitumor activity of immune checkpoint blocking antibodies against programmed death 1 (PD-1) in basal cell carcinoma (BCC) has been described. IO103 is a peptide vaccine against the major PD-1 ligand PD-L1. A phase IIa study of vaccination with IO103 and Montanide adjuvant was conducted in patients with resectable BCC (NCT03714529). Vaccinations were given six times every 2 weeks (q2w), followed by three vaccines q4w in responders. Primary endpoints were clinical responses of target tumors, change in target tumor size and immune responses to the vaccine. Secondary endpoint was safety. One tumor per patient was designated target tumor and biopsied twice during the course of vaccination. Synchronous non-target BCCs were not biopsied during vaccinations. Ten patients were vaccinated (six patients received six vaccinations and four patients received nine vaccinations). A partial response (PR) was seen in two target tumors. Two complete responses (CR) and one PR were observed in eight non-target tumors in four patients. No tumors progressed. Related adverse events were grade 1 and reversible. Immune responses against IO103 were induced in blood samples from nine of ten and skin-infiltrating lymphocytes from five of the nine patients. The regressions seen in non-target tumors suggest that IO103 may be effective against a subtype of BCC

Rectal cancer survival in the Nordic countries and Scotland

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldThe aim of this study was to present detailed population-based survival estimates for patients with a rectal adenocarcinoma, using cancer register data supplemented with clinical data. Based on cancer register data, differences in rectal cancer survival have been reported between countries in Europe. Variation in the distribution of stage at diagnosis, initial therapy including surgical technique, and comorbidity are possible explanatory factors. Adenocarcinomas in the rectum, diagnosed in 1997 and identified in the national cancer registries in the Nordic countries and Scotland were included. Age standardized 5-year relative survival and multiplicative regression models for the relative excess mortality were calculated. 3888 patients were included in the survival study. Men in Denmark, Finland and Iceland had lower 5-year relative survival and poorer stage distribution compared to Norway, Sweden and Scotland. Danish men had the highest rate of excess deaths in the first six months after diagnosis. Stage adjusted, the elevated relative excess mortality decreased and after six months the excess mortality rates were the same in all countries. The poor 5-year relative survival in Danish men was mainly due to a high excess rate of death during the first six months after diagnosis. The low survival in Finland and Iceland was not in accordance with other periods. For both countries this may be explained by random variation due to small numbers. The study emphasizes the need for high quality and detailed data in order to understand international survival differences, and cautions comparisons between large national samples and those of smaller areas

A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma

Anti-programmed death (PD)-1 (aPD1) therapy is an effective treatment for metastatic melanoma (MM); however, over 50% of patients progress due to resistance. We tested a first-in-class immune-modulatory vaccine (IO102/IO103) against indoleamine 2,3-dioxygenase (IDO) and PD ligand 1 (PD-L1), targeting immunosuppressive cells and tumor cells expressing IDO and/or PD-L1 (IDO/PD-L1), combined with nivolumab. Thirty aPD1 therapy-naive patients with MM were treated in a phase 1/2 study (https://clinicaltrials.gov/, NCT03047928). The primary endpoint was feasibility and safety; the systemic toxicity profile was comparable to that of nivolumab monotherapy. Secondary endpoints were efficacy and immunogenicity; an objective response rate (ORR) of 80% (confidence interval (CI), 62.7–90.5%) was reached, with 43% (CI, 27.4–60.8%) complete responses. After a median follow-up of 22.9 months, the median progression-free survival (PFS) was 26 months (CI, 15.4–69 months). Median overall survival (OS) was not reached. Vaccine-specific responses assessed in vitro were detected in the blood of >93% of patients during vaccination. Vaccine-reactive T cells comprised CD4(+) and CD8(+) T cells with activity against IDO- and PD-L1-expressing cancer and immune cells. T cell influx of peripherally expanded T cells into tumor sites was observed in responding patients, and general enrichment of IDO- and PD-L1-specific clones after treatment was documented. These clinical efficacy and favorable safety data support further validation in a larger randomized trial to confirm the clinical potential of this immunomodulating approach

Evaluation of the VeriStrat (R) serum protein test in patients with advanced squamous cell carcinoma of the lung treated with second-line afatinib or erlotinib in the phase III LUX-Lung 8 study

WOS: 000405152800017PubMed ID: 28577938Objectives: Identification of biomarkers associated with clinical benefit may be crucial in establishing optimal treatment choice for patients with squamous cell carcinoma (SCC) of the lung after first-line chemotherapy. In this study, the ability of the VeriStrat serum protein test to predict differential clinical benefit with afatinib versus erlotinib, and the association of VeriStrat status with clinical outcomes irrespective of EGFR-TKI used, was assessed in a retrospective analysis of the phase III LUX-Lung 8 trial. Materials and methods: Pretreatment plasma samples were analyzed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Spectra were evaluated to assign a VeriStrat 'Good' (VS-G) or VeriStrat 'Poor' (VS-P) classification. Overall survival (OS), progression-free survival, and other endpoints were assessed with respect to pretreatment VeriStrat status; OS was the primary efficacy variable. Results: Of 795 patients randomized in LUX-Lung 8, 675 were classified (VS-G: 412; VS-P: 263). In the VS-G group, OS was significantly longer with afatinib versus erlotinib (HR 0.79 [95% CI: 0.63-0.98]). In the VS -P group, there was no significant difference in OS between afatinib and erlotinib (HR 0.90 [0.70-1.16]). However, there was no interaction between VeriStrat classification and treatment group for OS la interaction = 0.5303). OS was significantly longer in VS-G versus VS -P patients, both in the overall VeriStrat-classified population (HR 0.41 [0.35-0.49]) and afatinib-treated patients (HR 0.40 [0.31-0.51]). Multivariate analysis showed that VeriStrat was an independent predictor of OS in afatinib-treated patients, regardless of ECOG PS or best response to first line chemotherapy. Outcomes with other efficacy endpoints were similar. Conclusion: VS-G classification is strongly associated with favorable survival outcomes with either afatinib or erlotinib compared with VS-P classification. In VS-G patients, survival outcomes with afatinib are superior to those with erlotinib. VeriStrat classification may guide treatment decisions in patients with SCC of the lung.Boehringer IngelheimBoehringer IngelheimThis study was funded by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version

Second-Line Afatinib versus Erlotinib for Patients with Squamous Cell Carcinoma of the Lung (LUX-Lung 8): Analysis of Tumor and Serum Biomarkers

WOS: 00041305580248

Association of ERBB Mutations With Clinical Outcomes of Afatinib- or Erlotinib-Treated Patients With Lung Squamous Cell Carcinoma Secondary Analysis of the LUX-Lung 8 Randomized Clinical Trial

WOS: 000444765300010PubMed ID: 29902295IMPORTANCE Treatment choice for lung squamous cell carcinoma could be aided by identifying predictive biomarkers. OBJECTIVE To assess whether patient outcomes in the LUX-Lung 8 trial were associated with ERBB gene family member aberrations in tumor specimens. DESIGN, SETTING, AND PARTICIPANTS Ad hoc secondary analysis of the LUX-Lung 8 trial conducted at 183 centers in 23 countries from March 30, 2012, to January 30, 2014. Eligible patients had stage IIIB or IV lung squamous cell carcinoma with progressive disease after 4 or more cycles of platinum-based chemotherapy. Tumor genetic analysis (TGA) was performed using next-generation sequencing in a cohort enriched for patients with progression-free survival (PFS) of more than 2 months. Epidermal growth factor receptor (EGFR) expression levels were assessed by immunohistochemistry in a separate cohort of patients from the LUX-Lung 8 population. Associations of PFS and overall survival (OS) with ERBB gene alterations and EGFR expression levels were assessed. This analysis was conducted from February 26, 2015, to June 12, 2017. INTERVENTIONS Patients were randomized 1:1 to treatment with afatinib dimaleate (40mg/d; n = 398) or erlotinib hydrochloride (150mg/d; n = 397). MAIN OUTCOMES AND MEASURES Overall survival, PFS, pooled and individual ERBB gene mutations, ERBB copy number alterations, and EGFR expression. RESULTS Tumor specimens from 245 patients were eligible for next-generation sequencing (TGA subset: 132 patients treated with afatinib; 113 patients treated with erlotinib). In this population, outcomes were improved with afatinib vs erlotinib treatment (PFS: median, 3.5 vs 2.5 months; hazard ratio [HR], 0.69; 95% CI, 0.51-0.92; P = .01; OS: median, 8.4 vs 6.6 months; HR, 0.81; 95% CI, 0.62-1.05; P = .12). Of 245 patients in the TGA subset, 53 (21.6%) had tumors with 1 or more ERBB mutations. Among afatinib-treated patients, PFS (median, 4.9 vs 3.0 months; HR, 0.62; 95% CI, 0.37-1.02; P = .06) and OS (median, 10.6 vs 8.1 months; HR, 0.75; 95% CI, 0.47-1.17; P = .21) were longer among those with ERBB mutation-positive disease than among those without. The presence of HER2 mutations was associated with favorable PFS and OS following afatinib vs erlotinib treatment. There was no apparent association between copy number alteration or EGFR expression level and outcome. CONCLUSIONS AND RELEVANCE Next-generation sequencingmay help identify patients with lung squamous cell carcinoma who would derive additional benefit from treatment with afatinib. The role of ERBB mutations, particularly HER2 mutations, as predictive biomarkers for afatinib treatment in this setting warrants further evaluation.Boehringer IngelheimBoehringer IngelheimThis study was funded by Boehringer Ingelheim