A multicenter study evaluating efficacy of immune checkpoint inhibitors in advanced non-colorectal digestive cancers with microsatellite instability.

BACKGROUND: One randomized phase III trial comparing chemotherapy (CT) with immune checkpoint inhibitors (ICI) has demonstrated significant efficacy of ICI in deficient DNA mismatch repair system/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer. However, few studies have compared ICI with CT in other advanced dMMR/MSI-H digestive tumors. METHODS: In this multicenter study, we included patients with advanced dMMR/MSI-H non-colorectal digestive tumors treated with chemotherapy and/or ICIs. Patients were divided retrospectively into two groups, a CT group and an immunotherapy (IO) group. The primary endpoint was progression-free survival (PFS). A propensity score approach using the inverse probability of treatment weighting (IPTW) method was applied to deal with potential differences between the two groups. RESULTS: 133 patients (45.1/27.1/27.8% with gastric/small bowel/other carcinomas) were included. The majority of patients received ICI in 1st (29.1%) or 2nd line (44.4%). The 24-month PFS rates were 7.9% in the CT group and 71.2% in the IO group. Using the IPTW method, IO treatment was associated with better PFS (HR=0.227; 95% CI 0.147-0.351; p < 0.0001). The overall response rate was 26.3% in the CT group versus 60.7% in the IO group (p < 0.001) with prolonged duration of disease control in the IO group (p < 0.001). In multivariable analysis, predictive factors of PFS for patients treated with IO were good performance status, absence of liver metastasis and prior primary tumor resection, whereas no association was found for the site of the primary tumor. CONCLUSIONS: In the absence of randomized trials, our study highlights the superior efficacy of ICI compared with standard-of-care therapy in patients with unresectable or metastatic dMMR/MSI-H non-colorectal digestive cancer, regardless of tumor type, with acceptable toxicity.

Atezolizumab plus modified docetaxel, cisplatin, and fluorouracil as first-line treatment for advanced anal cancer (SCARCE C17-02 PRODIGE 60): a randomised, non-comparative, phase 2 study.

BACKGROUND: The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2 study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus. METHODS: In this randomised, open-label, non-comparative, phase 2 study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m2 docetaxel and 40 mg per m2 cisplatin on day 1 and 1200 mg per m2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This trial is registered with ClinicalTrials.gov, NCT03519295, and is closed to new participants. FINDINGS: 97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8-28·4). The median age of participants was 64·1 years (IQR 56·2-71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35-55) in group A and 43% (29-58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47-100) in group A and 40% (19-85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3-4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths. INTERPRETATION: Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies. FUNDING: GERCOR, Roche.

DCF versus doublet chemotherapy as first-line treatment of advanced squamous anal cell carcinoma: a multicenter propensity score-matching study.

Triplet DCF (docetaxel, cisplatin and 5-flurouracil) and doublet CP/CF (carboplatin and paclitaxel/cisplatin and 5-fluorouracil) regimens were prospectively evaluated in advanced squamous anal cell carcinoma (SCCA), and validated as standard treatments. Even though the high efficacy and good tolerance of DCF regimen were confirmed in 3 independent prospective trials, doublet CP regimen is still recommended in several guidelines based in its better safety profile with similar efficacy compared to CF regimen. We performed a propensity score-adjusted method with inverse probability of treatment weighted (IPTW) and matched case control (MCC) comparison among patients with metastatic or non-resectable locally advanced recurrent SCCA, treated with chemotherapy as first line regimen. The primary endpoint was the overall survival (OS), and the secondary endpoint was the progression-free survival (PFS). 247 patients were included for analysis. 154 patients received DCF and 93 patients received a doublet regimen. The median OS was 32.3 months with DCF and 18.3 months with doublet regimens (HR 0.53, 95%CI 0.38-0.74; p = 0.0001), and the median PFS was 11.2 months with DCF versus 7.6 months with doublet regimens (HR 0.53, 95%CI 0.39-0.73; p < 0.0001). The hazard ratios by IPTW and MCC analyses were 0.411 (95% CI, 0.324-0.521; p < 0.0001) and 0.406 (95% CI, 0.261-0.632; p < 0.0001) for OS, and 0.466 (95% CI, 0.376-0.576; p < 0.0001) and 0.438 (95% CI, 0.298-0.644; P < 0.0001) for PFS. The triplet DCF regimen provides a high and significant benefit in OS and PFS over doublet regimens, and should be considered as upfront treatment for eligible patients with advanced SCCA.

Durable response of lung carcinoma patients to EGFR tyrosine kinase inhibitors is determined by germline polymorphisms in some immune-related genes.

BACKGROUND: Non-small cell lung cancer is a very poor prognosis disease. Molecular analyses have highlighted several genetic alterations which may be targeted by specific therapies. In clinical practice, progression-free survival on EGFR TKI treatment is between 12 and 14 months. However, some patients progress rapidly in less than 6 months, while others remain free of progression for 16 months or even longer during EGFR TKI treatment. METHODS: We sequenced tumor exomes from 135 lung cancer patients (79 with EGFR-wildtype (WT), 56 with EGFR-mutant tumors) enrolled in the ALCAPONE trial (genomic analysis of lung cancers by next generation sequencing for personalized treatment). RESULTS: Some germline polymorphisms were enriched in the EGFR-mutant subset compared to EGFR-WT tumors or to a reference population. However, the most interesting observation was the negative impact of some germline SNPs in immunity-related genes on survival on EGFR TKI treatment. Indeed, the presence of one of three particular SNPs in the HLA-DRB5 gene was associated with a decreased PFS on EGFR TKI. Moreover, some SNPs in the KIR3DL1 and KIR3DL2 genes were linked to a decrease in both progression-free and overall survival of patients with EGFR-mutant tumors. CONCLUSION: Our data suggest that SNPs in genes expressed by immune cells may influence the response to targeted treatments, such as EGFR TKIs. This indicates that the impact of these cells may not be limited to modulating the response to immunotherapies. Further studies are needed to determine the exact mechanisms underlying this influence and to identify the associated predictive and prognostic markers that would allow to refine treatments and so improve lung cancer patient outcomes. TRIAL REGISTRATION: NCT02281214: NGS Genome Analysis in Personalization of Lung Cancer Treatment (ALCAPONE).

Modified DCF (Docetaxel, Cisplatin and 5-fluorouracil) chemotherapy is effective for the treatment of advanced rectal squamous cell carcinoma.

Background: Advanced rectal squamous cell carcinoma (rSCC) is a very rare and aggressive entity, and the best initial management is crucial for long survival as well as organ preservation and quality of life. Whereas local diseases are treated with chemo-radiotherapy and salvage surgery, data are scarce on how to treat more advanced diseases, and the role of induction chemotherapy is unknown. Methods: We retrospectively analyzed all consecutive patients with advanced rSCC and treated with modified DCF (docetaxel, cisplatin, 5-fluorouracil; mDCF) regimen, from January 2014 and December 2021 in two French centers. Exploratory endpoints were efficacy (overall survival, recurrence-free survival, response rate, organ preservation rate) and safety. Results: Nine patients with locally advanced or metastatic diseases received a mDCF regimen and were included for analysis. The median age was 62.0 years, 7 patients (77.8%) were women, and all eight available tumors were positive for HPV, mostly (85.7%) to genotype 16. With a median follow-up of 33.1 months, 77.8% of patients were still alive and disease-free, and the median overall survival was not reached at six years. The objective response rate was 87.5% after mDCF, and the complete response rate was 25.0% after mDCF and was increased to 75.0% after chemoradiotherapy. Only one patient underwent surgery on the primary tumor, with a complete pathological response. The median mDCF cycle was eight over eight scheduled, and all patients received the complete dose of radiotherapy without interruptions. Conclusions: Induction mDCF chemotherapy followed by chemoradiotherapy is safe and highly effective in patients with advanced rSCC, and should be considered as an option in metastatic stage or locally advanced disease with an organ-preservation strategy.

Prognostic role of HPV integration status and molecular profile in advanced anal carcinoma: An ancillary study to the epitopes-HPV02 trial.

Squamous Cell Carcinoma of the Anal canal (SCCA) is a rare disease associated with a Human Papillomavirus (HPV) infection in most cases, predominantly the HPV16 genotype. About 15% of SCCA are diagnosed in metastatic stage and some will relapse after initial chemoradiotherapy (CRT). Treatment of patients by Docetaxel, Cisplatin and 5-fluorouracil (DCF) has been recently shown to improve their complete remission and progression-free survival. The aim of this retrospective study was to explore the impact of HPV infection, HPV DNA integration, TERT promoter mutational status and somatic mutations of oncogenes on both progression-free (PFS) and overall survivals (OS) of patients treated by DCF. Samples obtained from 49 patients included in the Epitopes-HPV02 clinical trial, diagnosed with metastatic or non-resectable local recurrent SCCA treated by DCF, were used for analyses. Median PFS and OS were not associated with HPV status. Patients with episomal HPV had an improved PFS compared with SCCA patients with integrated HPV genome (p=0.07). TERT promoter mutations were rarely observed and did not specifically distribute in a subset of SCCA and did not impact DCF efficacy. Among the 42 genes investigated, few gene alterations were observed, and were in majority amplifications (68.4%), but none were significantly correlated to PFS. As no biomarker is significantly associated with patients' survival, it prompts us to include every patient failing CRT or with metastatic disease in DCF strategy.

Phase II INTERACT-ION study: ezabenlimab (BI 754091) and mDCF (docetaxel, cisplatin, and 5-fluorouracil) followed by chemoradiotherapy in patients with Stage III squamous cell anal carcinoma.

Background: Chemoradiotherapy alone is the standard treatment for locally advanced squamous cell anal carcinoma (SCAC). However, up to 50% of patients will experience recurrence; thus, there is a need for new treatments to improve outcomes. Modified docetaxel, cisplatin and 5-fluorouracil (mDCF) is a treatment option for first-line metastatic SCAC, having shown efficacy in the Epitopes-HPV01 and -02 trials (NCT01845779 and NCT02402842). mDCF treatment also plays a role in the modulation of anti-tumor immunity, suggesting it may be a good combination partner for immunotherapy in patients with SCAC. Anti-programmed death protein-1 (PD-1) immunotherapy has been shown to be effective in metastatic SCAC. We therefore designed the INTERACT-ION study to assess the combination of mDCF with ezabenlimab (BI 754091), an anti-PD-1 antibody, followed by chemoradiotherapy, in patients with Stage III SCAC. Methods: INTERACT-ION is a pivotal, open-label, single-arm phase II study in patients with treatment-naïve Stage III SCAC. Patients will receive induction treatment with mDCF (docetaxel 40 mg/m2 and cisplatin 40 mg/m2 on Day 1, 5-fluorouracil 1200 mg/m2/day for 2 days) every 2 weeks for 4 cycles and ezabenlimab (240 mg given intravenously) every 3 weeks for 3 cycles. In the absence of disease progression at 2 months, two additional cycles of mDCF and one additional cycle of ezabenlimab will be administered. Patients with radiological objective response, pathological complete/near-complete response and biological complete response will then receive an involved-node radiotherapy with intensity-modulated radiation therapy and concurrent chemotherapy, followed by ezabenlimab alone for seven cycles. All other patients will receive standard chemoradiotherapy. The primary endpoint is the clinical complete response rate 10 months after the first cycle of mDCF plus ezabenlimab. Major secondary endpoints are major pathological response and biological complete response after induction treatment. An extensive ancillary biomarker study in tumor tissue and peripheral blood will also be conducted. Discussion: The addition of immunotherapy to chemotherapy is an area of active interest in metastatic anal cancer. This pivotal study will evaluate this combination in the locally advanced setting. Ancillary biomarker studies will contribute to the understanding of predictors of response or resistance to treatment. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04719988, identifier NCT04719988.

Long-Term Disease Control After locoregional Pelvic Chemoradiation in Patients with Advanced Anal Squamous Cell Carcinoma.

Introduction: The incidence of metastatic squamous cell carcinoma of the anus (SCCA) is increasing. Even if systemic docetaxel, cisplatin, and 5-Fluorouracil (DCF) provide a high rate of long-term remission, the role of pelvic chemoradiation (CRT) is unknown in this setting. We reported the safety and efficacy of local CRT in patients with synchronous metastatic SCCA who achieved objective response after upfront DCF. Methods: Patients included in Epitopes HPV01 or Epitopes HPV02 or SCARCE trials and treated with DCF followed by pelvic CRT were included. Concurrent chemotherapy was based on mitomycin (MMC) (10 mg/m² for two cycles) and fluoropyrimidine (capecitabine 825 mg/m² twice a day at each RT treatment day or two cycles of intra-venous 5FU 1000 mg/m² from day 1 to day 4). Primary endpoints were safety, local complete response rate, and local progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and metastasis-free survival (MFS). Results: From 2013 to 2018, 16 patients received DCF followed by a complementary pelvic CRT for advanced SCCA. Median follow-up was 42 months [range, 11-71]. All patients received the complete radiation dose. Compliance to concurrent CT was poor. Overall, 13/15 of the patients (87%) had at least one grade 1-2 acute toxicity and 11/15 of the patients (73%) had at least one grade 3-4 toxicity. There was no treatment-related death. The most frequent grade 3-4 adverse effects were neutropenia (36%), dermatitis (40%), and anitis (47%). Eleven patients (73%) had at least one chronic grade 1 or 2 toxicity. One patient had a grade 4 chronic rectitis (7%). Complete local response rate was 81% at first evaluation and 62.5% at the end of the follow-up. Median local PFS was not reached and the 3-year local PFS was 77% (95%CI 76.8-77). Conclusions: In patients with metastatic SCCA who had a significant objective response after upfront DCF, local CRT was feasible with high complete local response rate. The good local control rate, despite interruptions due to toxicities and low CT compliance, underline the role of pelvic RT. The high rate of toxicity prompts the need to adapt CRT regimen in the metastatic setting.

A Phase II Study Evaluating the Interest to Combine UCPVax, a Telomerase CD4 TH1-Inducer Cancer Vaccine, and Atezolizumab for the Treatment of HPV Positive Cancers: VolATIL Study.

Background: There is a strong rational of using anti-programmed cell death protein-1 and its ligand (anti-PD-1/L1) antibodies in human papillomavirus (HPV)-induced cancers. However, anti-PD-1/L1 as monotherapy induces a limited number of objective responses. The development of novel combinations in order to improve the clinical efficacy of an anti-PD-1/L1 is therefore of interest. Combining anti-PD-1/L1 therapy with an antitumor vaccine seems promising in HPV-positive (+) cancers. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (hTERT, human telomerase reverse transcriptase). UCPVax is being evaluated in a multicenter phase I/II study in NSCLC (non-small cell lung cancer) and has demonstrated to be safe and immunogenic. The aim of the VolATIL study is to evaluate the combination of atezolizumab (an anti-PD-L1) and UCPVax vaccine in a multicenter phase II study in patients with HPV+ cancers. Methods: Patients with HPV+ cancer (anal canal, head and neck, and cervical or vulvar), at locally advanced or metastatic stage, and refractory to at least one line of systemic chemotherapy are eligible. The primary end point is the objective response rate (ORR) at 4 months. Patients will receive atezolizumab every 3 weeks at a fixed dose of 1,200 mg in combination with the UCPVax vaccine at 1 mg subcutaneously. Discussion: Anti-cancer vaccines can restore cancer-immunity via the expansion and activation of tumor-specific T cells in patients lacking pre-existing anti-tumor responses. Moreover, preclinical data showed that specific TH1 CD4 T cells sustain the quality and homing of an antigen-specific CD8+ T-cell immunity. In previous clinical studies, the induction of anti-hTERT immunity was significantly correlated to survival in patients with advanced squamous anal cell carcinoma. Thus, there is a strong rational to combine an anti-cancer hTERT vaccine and an immune checkpoint inhibitor to activate and promote antitumor T-cell immunity. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a telomerase-based TH1 inducing vaccine (UCPVax) and an anti-PD-L1 (atezolizumab) immunotherapy in HPV+ cancers, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials. Clinical Trial Registration: https://www.clinicaltrials.gov/, identifier NCT03946358.

Immunotherapy in MSI/dMMR tumors in the perioperative setting: The IMHOTEP trial.

BACKGROUND: Immune checkpoint inhibitors (ICI) targeting Programmed death-1 (PD-1) have shown their efficacy in advanced MSI/dMMR (microsatellite instability/deficient mismatch repair) tumors. The MSI/dMMR status predicts clinical response to ICI. The promising results evaluating ICI in localized MSI/dMMR tumors in neoadjuvant setting need to be confirmed in MSI/dMMR solid tumors. The aim of the IMHOTEP trial is to assess the efficacy of neoadjuvant anti-PD-1 treatment in MSI/dMMR tumors regarding the pathological complete response rate. METHODS: This study is a prospective, multicenter, phase II study including 120 patients with localized MSI/dMMR carcinomas suitable for curative surgery. A single dose of pembrolizumab will be administered before the surgery planned 6 weeks later. Primary objective is to evaluate the efficacy of neoadjuvant pembrolizumab according to pathological complete tumor response. Secondary objectives are to assess safety, recurrence-free survival and overall survival. Ancillary studies will assess molecular and immunological biomarkers predicting response/resistance to ICI. First patient was enrolled in December 2021. DISCUSSION: The IMHOTEP trial will be one of the first clinical trial investigating perioperative ICI in localized MSI/dMMR in a tumor agnostic setting. Assessing neoadjuvant anti-PD-1 is mandatory to improve MSI/dMMR patient's outcomes. The translational program will explore potential biomarker to improve our understanding of immune escape and response in this ICI neoadjuvant setting.

Impact of trough concentrations of regorafenib and its major metabolites M-2 and M-5 on overall survival of chemorefractory metastatic colorectal cancer patients: Results from a multicentre GERCOR TEXCAN phase II study.

PURPOSE: This prospective pharmacokinetic (PK) ancillary study of the TEXCAN phase II GERCOR trial of patients with chemorefractory metastatic colorectal cancer and treated with regorafenib (REGO) investigated correlations between overall survival (OS) and concentrations (C) of REGO and its active metabolites, M-2 and M-5. METHODS: 55 patients received REGO 160 mg/day for 21 days of a 28-day cycle (NCT02699073). REGO, M-2, M-5 were measured by liquid chromatography-mass spectrometry assay on day 15 of cycle 1 (C1) and 2 (C2). We studied the association between OS and Cmin of REGO, M-2 and M-5 at C1 and their accumulations between C1 and C2. RESULTS: Medians of C2/C1 M-2 and M-5 ratios were 0.82 (interquartile range 0.50-1.78) and 0.75 (interquartile range 0.41-1.93), respectively. Patients with C2/C1 M-2 ratio ≥ median had improved survival compared to those < median (12.6 versus 4.0 months, P = 0.023), corresponding to a 66% mortality risk reduction in multivariate analysis. The C2/C1 M-2 ratio correlated with C1 REGO+M-2+M-5 (Csum; P = 0.006). Restricted cubic spline analysis showed an increased OS benefit as the C2/C1 M-2 ratio raises and when C1 Csum ranged between 2.5 and 5.5 mg/L. Patients within the Csum range had a reduced incidence of serious adverse events and improved OS. CONCLUSIONS: We identified PK parameters associated with a survival benefit in patients with metastatic colorectal cancer treated by REGO. OS and safety were favourable when C1 REGO+M-2+M-5 Csum ranged between 2.5 and 5.5 mg/L. These results pave the way for individual REGO dose modification strategies based on PK monitoring. CLINICAL TRIAL REFERENCE: NCT02699073.

Interest of the Addition of Taxanes to Standard Treatment in First-Line Advanced HER2 Positive Gastroesophageal Adenocarcinoma in Selective Patients.

Background: Studies have reported a beneficial role of the addition of trastuzumab to platin-5-FU based chemotherapy in first-line advanced HER2 positive gastroesophageal adenocarcinoma (GEA). However, the effect of taxanes combined with platin-5FU + trastuzumab (PFT) is understudied. Methods: We performed a retrospective cohort study to evaluate the interest of taxanes among HER2-positive advanced GEA patients treated with PFT. We enrolled HER2-positive advanced GEA patients who underwent treatment between January 2009 to March 2021 in seven hospitals centers in France, treated with PFT alone (S group) or with taxanes + PFT regimen (T group). The primary outcome was progression-free survival (PFS). Also, overall survival (OS), response rate, conversion surgery rate, and safety were evaluated. Results: Overall, 65 patients received PFT-based therapy, 24 patients in the T group, and 41 patients in the S group. To avoid the selection bias, only those patients presenting an ECOG-PS of 0-1 and synchronous metastasis (21 patients in the T group and 19 patients in the S group) were included for analysis. The median PFS was 9.3 months (95%CI 7.0 to 17.2) in the T group and 5.9 months (95%CI 3.7 to 9.6) in the S group (log-rank p=0.038). Treatment by taxanes was significantly associated with a better PFS in univariate (HR 0.49; 95%CI 0.25 to 0.98, p=0.042) and multivariate Cox regression analysis (HR 0.44; 95%CI 0.21 to 0.94, p=0.033), and IPTW method (HR 0.56; 95% CI 0.34 to 0.91, p=0.019). OS was prolonged (19.0 months (95%CI 7.8 to 45.2) vs 13.0 months (95%CI 5.5 to 14.8), log-rank p=0.033) in favor of the T group. Treatment by taxanes was significantly associated with a better OS in univariate Cox regression analysis (HR 0.49; 95%CI 0.21 to 0.96, p=0.038) and IPTW method (HR 0.49; 95% CI 0.29 to 0.84, p=0.009). The response rate was higher in the T group, with conversion surgery in five patients. No treatment-related death was observed in both groups. Conclusions: Given the improvement in PFS and OS, the addition of taxanes to standard chemotherapy could be considered as a promising treatment for selected HER2-positive advanced GEA patients, with PS 0-1 and synchronous metastasis (NCT04920747).

Second-line treatment after docetaxel, cisplatin and 5-fluorouracil in metastatic squamous cell carcinomas of the anus. Pooled analysis of prospective Epitopes-HPV01 and Epitopes-HPV02 studies.

BACKGROUND: Squamous cell carcinoma of the anus (SCCA) is a rare disease often diagnosed at a localised stage. For locally advanced recurrence or metastatic disease, DCF (docetaxel, cisplatin, 5-fluorouracil) demonstrated high efficacy and became one of the standard regimens. However, there is no standard of care in the second line. PATIENTS AND METHODS: In the Epitopes-HPV01 and Epitopes-HPV02 prospective trials, 115 patients with advanced SCCA were treated with a DCF regimen in the first line. In these studies, second-line data were registered per protocol. RESULTS: After a median follow-up of >40 months, at progression, 73 patients received a second-line (L2) treatment. In this L2 population, median overall survival (mOS) was 13.5 months (95%CI 9.4-19.8), and median progression-free survival (mPFS) was 5.7 months (3.4-7.3) in L2. Fourteen patients presented an oligometastatic progression and were treated with an ablative treatment (surgery or radiotherapy); mOS was 48.3 months (NE-NE), and mPFS was 31.3 months (23.2-NE). Fifty-nine patients received a systemic treatment (chemotherapy or immunotherapy); mOS was 11 months (8.4-15.4) and mPFS was 4.9 months (3.3-7). The most frequent chemotherapy regimens were the reintroduction of DCF, paclitaxel, FOLFIRI and mitomycin plus fluoropyrimidine. No significant difference was observed between regimens (p = 0.26). Six patients received anti-PD1/L1-based immunotherapy. CONCLUSION: Second-line treatments are effective in patients with SCCA. Ablative treatment is feasible and is probably the best option for patients with oligometastatic progression. If this is not possible, systemic therapy by an anti-PD1/L1 immunotherapy or chemotherapy can be recommended. Reintroduction of DCF, paclitaxel, FOLFIRI or mitomycin-C plus fluoropyrimidine are possible options.

Efficacy and safety of cabozantinib for patients with advanced hepatocellular carcinoma based on albumin-bilirubin grade.

BACKGROUND: Albumin-bilirubin (ALBI) grade is an objective measure of liver function for patients with hepatocellular carcinoma (HCC). The tyrosine kinase inhibitor cabozantinib is approved for patients with advanced HCC who have received prior sorafenib based on the phase 3 CELESTIAL trial (NCT01908426). Cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated HCC. METHODS: Patients were randomised 2:1 to receive cabozantinib 60 mg or placebo orally every day. Clinical outcomes in patients with ALBI grade 1 or 2 at baseline were evaluated in CELESTIAL. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin, with an ALBI grade of 1 defined as ≤ -2.60 score and a grade of 2 as a score of > -2.60 to ≤ -1.39. RESULTS: Cabozantinib improved OS and PFS versus placebo in both ALBI grade 1 (hazard ratio [HR] [95% CI]: 0.63 [0.46-0.86] and 0.42 [0.32-0.56]) and ALBI grade 2 (HR [95% CI]: 0.84 [0.66-1.06] and 0.46 [0.37-0.58]) subgroups. Adverse events were consistent with those in the overall population. Rates of grade 3/4 adverse events associated with hepatic decompensation were generally low and were more common among patients in the ALBI grade 2 subgroup. DISCUSSION: These results provide initial support of cabozantinib in patients with advanced HCC irrespective of ALBI grade 1 or 2. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT01908426.

Present and Future Research on Anal Squamous Cell Carcinoma.

Squamous cell carcinoma of the anus is an orphan disease, and after more than three decades of no substantial advances in disease knowledge and treatment, it is finally gaining momentum with the arrival of a taxane-based chemotherapy and immunotherapy. Currently, about 20 combination clinical trials with an anti-PD1/L1 are ongoing in localized and advanced stages, in association with radiotherapy, chemotherapy, tumor vaccines, anti-CTLA4, anti-EGFR, or antiangiogenic molecules. Moreover, a new biomarker with high sensitivity and specificity such as HPV circulating tumor DNA (HPV ctDNA) by liquid biopsy, is improving not only the prognostic measurement but also the treatment strategy guidance for this disease. Finally, better understanding of potential targets is reshaping the present and future clinical research in this unique, HPV genotype-16-related disease in the great majority of patients.

Pembrolizumab with Capox Bevacizumab in patients with microsatellite stable metastatic colorectal cancer and a high immune infiltrate: The FFCD 1703-POCHI trial.

Pembrolizumab, a PD1 immune checkpoint inhibitor (ICI), was recently reported to be very effective in patients with microsatellite instable/deficient mismatch repair metastatic colorectal cancer (MSI/dMMR mCRC), unlike patients with microsatellite stable/proficient MMR (MSS/pMMR) mCRC, in whom ICIs are generally ineffective. However, about 15% of MSS/pMMR CRCs are highly infiltrated by tumour infiltrating lymphocytes. In addition, both oxaliplatin and bevacizumab have been shown to have immunomodulatory properties that may increase the efficacy of an ICI. We formulated the hypothesis that patients with MSS/pMMR mCRC with a high immune infiltrate can be sensitive to ICI plus oxalipatin and bevacizumab-based chemotherapy. POCHI is a multicenter, open-label, single-arm phase II trial to evaluate efficacy of Pembrolizumab with Capox Bevacizumab as first-line treatment of MSS/pMMR mCRC with a high immune infiltrate for which we plan to enrol 55 patients. Primary endpoint is progression-free survival (PFS) at 10 months, which is expected greater than 50%, but a 70% rate is hoped for. Main secondary objectives are overall survival, secondary resection rate and depth of response. Patients must have been resected of their primary tumour so as to evaluate two different immune scores (Immunoscore® and TuLIS) and are eligible if one score is "high". The first patient was included on April 20, 2021.

Real-world safety and effectiveness of regorafenib in metastatic colorectal cancer: the French CORRELATE cohort.

Aim: We report real-world evidence with regorafenib in previously treated metastatic colorectal cancer from the French cohort of the international, prospective, observational CORRELATE study. Patients & methods: Patients receiving regorafenib according to French health authority approval were included. The primary end point was treatment-emergent adverse events. Overall survival and progression-free survival were secondary end points. Results: Two hundred and forty-two patients (61% male, median age: 66 years) were enrolled. The most common grade ≥3 drug-related treatment-emergent adverse events were hand-foot skin reaction (10.3%), asthenia/fatigue (9.9/1.2%) and hypertension (6.2%). Median overall survival and progression-free survival were 6.8 (95% CI: 6.3-7.6) and 2.8 months (95% CI: 2.6-3.0), respectively. Conclusion: The real-world safety and effectiveness data of regorafenib in metastatic colorectal cancer in France align with findings from Phase III clinical trials and the global CORRELATE population.

Study of the SARS-CoV-2-specific immune T-cell responses in COVID-19-positive cancer patients.

BACKGROUND: Cancer patients are considered highly vulnerable to the COVID-19 pandemic. However, delaying cancer-specific therapies could have a deleterious effect on survival. The potential suppressive effects of chemotherapies or cancer-related microenvironment raised the question on how cancer patients' immune system responds to SARS-CoV-2 virus. METHODS: We have started a prospective monocentric trial entitled COV-CREM (NCT04365322) in April 2020. The primary objective of the trial was to assess specific immune response's intensity and diversity to SARS-CoV-2 in infected patients. RESULTS: In this study, we showed that cancer patients (28 solid tumours, 11 haematological malignancies) exposed to SARS-CoV-2 produced a high rate of specific antibodies, as observed in patients without a cancer history (n = 29). However, our results highlight a lack in the generation of T-cell responses against CoV-N, M and S proteins from the SARS-CoV-2 virus, suggesting that cancer patients failed to mount a protective T-cell immunity. Nevertheless, SARS-CoV-2 infection did not impair established immune memory since specific responses against common viruses were not hampered in cancer patients. CONCLUSION: Given the severity and the unknown evolution of the ongoing COVID-19 pandemic, it is of fundamental importance to integrate cancer patients in vaccination programs.

[Squamous cell anal carcinoma. What's next ?] / Cancer épidermoïde du canal anal métastatique en 2020.

Despite its status as a rare disease, the incidence of the squamous cell carcinoma of the anus (SCCA) is surging, especially in its metastatic form. In addition, the prognosis of initially localized diseases has not substantially changed since the 1970s with a recurrence rate of between 25-40 % after the chemoradiotherapy. The updated data from 115 patients included in the Epitopes-HPV01 and Epitopes-HPV02 trials, confirm the modified regimen of DCF (mDCF) as the treatment of choice for patients with advanced SCCA given the rate of sustained remissions and complete molecular responses observed. The carboplatin-paclitaxel regimen may be considered as an option for patients with contraindication to cisplatin or 5-FU. In chemo-refractory patients, the efficacy of anti-PD-1/PD-L1 in monotherapy is limited and only brings benefit to 10-20 % of patients, and its use cannot be generalized in the absence of an association potentiating its effectiveness. In order to better understand the immunological parameters associated with advanced SCCA, an analysis of peripheral immune responses was carried out in the Epitopes-HPV01 and 02 trials. It demonstrated the key role of CD4 Th1 specific responses of telomerase and M-MDSC as main prognostic factors for the therapeutic efficacy of DCF. Numerous combination trials are currently underway or will soon begin in localized SCCA, as well as in the first and second-line in the advanced stage. Finally, the detection of circulating tumor DNA of HPV oncoprotein E6 and E7 (HPVtc), especially by the "digital droplet PCR" technique, is highly sensitive and specific, and can be used in daily practice.