Two Distinct Pathways to Development of Squamous Cell Carcinoma of the Vulva

Squamous cell carcinoma (SCC) accounts for approximately 95% of the malignant tumors of the vaginal vulva and is mostly found in elderly women. The future numbers of patients with vulvar SCC is expected to rise, mainly because of the proportional increase in the average age of the general population. Two different pathways for vulvar SCC have been put forth. The first pathway is triggered by infection with a high-risk-type Human Papillomavirus (HPV). Integration of the HPV DNA into the host genome leads to the development of a typical vulvar intraepithelial neoplasia (VIN), accompanied with overexpression of p14ARF and p16INK4A. This lesion subsequently forms a warty- or basaloid-type SCC. The HPV vaccine is a promising new tool for prevention of this HPV related SCC of the vulva. The second pathway is HPV-independent. Keratinizing SCC develops within a background of lichen sclerosus (LS) through a differentiated VIN. It has a different set of genetic alterations than those in the first pathway, including p53 mutations, allelic imbalances (AI), and microsatellite instability (MSI). Further clinical and basic research is still required to understand and prevent vulvar SCC. Capsule. Two pathway for pathogenesis of squamous cell carcinoma of the value are reviewed

FRESCO-2: a global Phase III study investigating the efficacy and safety of fruquintinib in metastatic colorectal cancer

Desenvolupament clínic; Fruquintinib; Càncer colorrectal metastàtic refractariDesarrollo clinico; Fruquintinib; Cáncer colorrectal metastásico refractarioClinical development; Fruquintinib; Refractory metastatic colorectal cancerFruquintinib, a novel, highly selective, small-molecule tyrosine kinase inhibitor of VEGF receptors (VEGFRs)-1, -2 and -3, is approved in China for the treatment of metastatic colorectal cancer. FRESCO-2, a global, randomized, double-blind, placebo-controlled, Phase III study, is investigating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Key inclusion criteria include: progression on or intolerance to TAS-102 and/or regorafenib; and prior treatment with approved chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy. Approximately 687 patients will be randomized 2:1 to fruquintinib plus best supportive care or placebo plus best supportive care. Primary and key secondary end points are overall survival and progression-free survival, respectively. FRESCO-2 is enrolling in the USA, Europe, Australia and Japan

Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer

Colorectal cancer; Metastasis; Targeted therapiesCáncer colorrectal; Metástasis; Terapias dirigidasCàncer de colorectal; Metàstasi; Teràpies dirigidesDESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published. Patients received T-DXd 6.4 mg/kg every 3 weeks and were assigned to either: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+), cohort B (IHC 2+/ISH−), or cohort C (IHC 1+). Primary endpoint was objective response rate (ORR) by independent central review in cohort A. Secondary endpoints included ORR (cohorts B and C), duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and safety of T-DXd. 86 patients were enrolled (53 in cohort A, 15 in cohort B, and 18 in cohort C). Results of the primary analysis are published, reporting an ORR of 45.3% in cohort A. Here, we report the final results. No responses occurred in cohorts B or C. Median progression-free survival, overall survival, and duration of response were 6.9, 15.5, and 7.0 months, respectively. Overall serum exposure (cycle 1) of T-DXd, total anti-HER2 antibody, and DXd were similar regardless of HER2 status. Most common grade ≥3 treatment-emergent adverse events were decreased neutrophil count and anemia. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 patients (9.3%). These findings support the continued exploration of T-DXd in HER2-positive mCRC.This study was sponsored by Daiichi Sankyo and funded by both Daiichi Sankyo and AstraZeneca. The sponsor was involved in data collection, analysis, interpretation, and preparation of the manuscript. We thank the patients who participated in this study, as well as their families and caregivers. We also thank the staff and investigators at all the study sites. We thank Masato Fukae, PhD, and Emi Kamiyama, PhD, for the analysis of the pharmacokinetic parameters, both of whom are employed by Daiichi Sankyo. Under the guidance of the authors, assistance in medical writing and editorial support was provided by Cindy M. Rigby, PhD, and Marianna B. Johnson, PhD, of ApotheCom, and was funded by Daiichi Sankyo

Health-related Quality of Life in the Phase III LUME-Colon 1 Study: Comparison and Interpretation of Results From EORTC QLQ-C30 Analyses

QVRS; Nintedanib; Temps de deterioramentCVRS; Nintedanib; Tiempo para el deterioroHRQoL; Nintedanib; Time to deteriorationIntroduction We used European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) data from the LUME-Colon 1 study to illustrate different methods of statistical analysis for health-related quality of life (HRQoL), and compared the results. Patients and Methods Patients were randomized 1:1 to receive nintedanib 200 mg twice daily plus best supportive care (n = 386) or matched placebo plus best supportive care (n = 382). Five methods (mean treatment difference averaged over time, using a mixed-effects growth curve model; mixed-effects models for repeated measurements (MMRM); time-to-deterioration (TTD); status change; and responder analysis) were used to analyze EORTC QLQ-C30 global health status (GHS)/QoL and scores from functional scales. Results Overall, GHS/QoL and physical functioning deteriorated over time. Mean treatment difference slightly favored nintedanib over placebo for physical functioning (adjusted mean, 2.66; 95% confidence interval [CI], 0.97-4.34) and social functioning (adjusted mean, 2.62; 95% CI, 0.66-4.47). GHS/QoL was numerically better with nintedanib versus placebo (adjusted mean, 1.61; 95% CI, −0.004 to 3.27). MMRM analysis had similar results, with better physical functioning in the nintedanib group at all timepoints. There was no significant delay in GHS/QoL deterioration (10%) and physical functioning (16%) with nintedanib versus placebo (TTD analysis). Status change analysis showed a higher proportion of patients with markedly improved GHS/QoL and physical functioning in the nintedanib versus placebo groups. Responder analysis showed a similar, less pronounced pattern. Conclusion Analyses of EORTC QLQ-C30 data showed that HRQoL was not impaired by treatment with nintedanib versus placebo. Analysis and interpretation of HRQoL endpoints should consider symptom type and severity and course of disease.This work was supported by Boehringer Ingelheim. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Syneos Health Communications during the preparation of this manuscript

Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC

Colorectal cancer; Encorafenib; Quality of lifeCáncer colorrectal; Encorafenib; Calidad de vidaCàncer colorectal; Encorafenib; Qualitat de vidaBackground In the BEACON CRC study (NCT02928224), encorafenib plus cetuximab with binimetinib {9.3 versus 5.9 months; hazard ratio (HR) [95% confidence interval (CI)]: 0.60 [0.47-0.75]} or without binimetinib [9.3 versus 5.9 months; HR (95% CI): 0.61 (0.48-0.77)] significantly improved overall survival (OS) compared with the previous standard of care (control) in patients with BRAF V600E metastatic colorectal cancer (mCRC). Quality of life (QoL) was a secondary endpoint, assessed using validated instruments. Patients and methods BEACON CRC was a randomized, open-label, phase III study comparing encorafenib plus cetuximab with or without binimetinib and the investigator’s choice of irinotecan plus cetuximab or FOLFIRI plus cetuximab (chemotherapy control) in patients with previously treated BRAF V600E mCRC. Patient-reported QoL assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC) and Functional Assessment of Cancer Therapy—Colorectal (FACT-C). The primary outcome for these tools was time to definitive 10% deterioration. Results Encorafenib plus cetuximab, both with and without binimetinib, was associated with longer median times to definitive 10% deterioration versus the control group in the EORTC Global Health Status scale [HR (95% CI): 0.65 (0.52-0.80) versus 0.61 (0.49-0.75), respectively] and the FACT-C functional well-being subscale [HR (95% CI): 0.62 (0.50-0.76) versus 0.58 (0.47-0.72), respectively]. Consistent results were observed across all subscales of the EORTC and FACT-C instruments. QoL was generally maintained during treatment for the global EORTC and FACT-C scales. Conclusions In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC.This study was sponsored by Array BioPharma Inc, which was acquired by Pfizer, United States; National Cancer Institute, United States in July 2019. This work was also supported by the Cancer Center Core Grant [grant number P30 CA 008748] to Memorial Sloan-Kettering Cancer Center

Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer

Asia; Colorectal cancer; PembrolizumabAsia; Cáncer colorrectal; PembrolizumabÀsia; Càncer colorectal; PembrolizumabThe phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1–57.8) months with pembrolizumab and 43.9 (range 36.6–55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months–NR) with pembrolizumab versus 10.4 (95% CI 6.3–22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26–1.20). Median OS was NR (range 13.8 months–NR) versus 30.0 (14.7–NR) months (HR 0.65, 95% CI 0.27–1.55) and ORR was 50% (95% CI 28–72) versus 46% (95% CI 27–67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002