Monalizumab (mona), a IgG4 Ab targeting the NKG2A receptor, has limited activity as monotherapy in RM SCCHN. Targeting the NKG2A-HLA-E pathway with PD(L)1 blockade improved tumor control in mice. Preliminary data of mona and durvalumab (durva), have shown encouraging activity in pretreated MSS colorectal cancer. The UPSTREAM trial is an umbrella trial of targeted therapies and immunotherapy for RM SCCHN (post platinum, ECOG 0-1). The immunotherapy 2 (I2) cohort was a phase II, randomized, open label substudy evaluating the efficacy of the combination of durva (iv, 1500mg Q4W) and mona (iv, 750mg Q2W or Q4W) (D+M) vs physician’s choice (control, ctrl) (2:1 ratio). Pts non-eligible for the biomarker-driven cohorts and pretreated with PD(L)1, were included in the I2 cohort. The primary endpoint was objective response rate (RECISTv1.1) during the first 16 weeks (2-stage Simon design applied to the D+M arm, H1 15%, H0 3%, 1-sided α 10%, power 90%). Secondary endpoints included response duration, toxicity, PFS, and OS. 66 RM SCCHN pts were included in the I2 cohort (D+M: n=45, ctrl: n=21). 61 pts were evaluable (D+M: n=43, ctrl: n=18): median age 62 yrs; oral cavity 20%, oropharynx 39%, hypopharynx 20%, larynx 21%; 87% with 2 or 3 previous lines. In D+M 1 partial response (PR) was recorded and stable disease (SD) was observed in 11 pts (26%). 1 PR was reported in the ctrl arm and SD in 8 (44%). The median PFS was 2.0 mo (95% CI: 1.8-2.4) and 3.1 mo (95% CI: 1.9-3.9) in the D+M arm and ctrl arm, respectively. The median OS was 4.4 mo (95% CI: 3.3-9.2) and 8.0 mo (95% CI: 3.1-14.9) in the D+M and ctrl arm, respectively. In the D+M arm, 4 pts (9%) reported grade >/= 3 treatment-related adverse events. The substudy of mona and durva did not meet its primary objective. No benefit was seen in PFS and OS. These are preliminary results, definitive results will be presented at the congress. ClinicalTrials.gov: NCT03088059.

Treatment of locoregional failures or second primary in HNSCC in previously irradiated areas is a challenge. Reirradiation is currently the only treatment which can improve disease-free survival (DFS) after salvage surgery (SS) even if it has no impact on the overall survival (OS) because of high toxicity, showing the need to investigate other adjuvant therapies (AT) such as immunotherapy. The objectives of this study were to evaluate the 2-year DFS and OS of patients (pts) treated with nivolumab (N) after SS, the toxicity of N in this population and to determine biomarkers of response. This multicentric non-randomized phase II add trial pts with recurrence or second primary of HNSCC in previously irradiated area, operated by SS with curative intent, more than 6 months after initial radiotherapy and of bad prognosis justifying an AT. Within 8 weeks of SS, 240 mg of adjuvant N was administrated every 2 weeks during the first 3 months, and then N 480 mg every 4 weeks was administrated for the next 3 months. The design was performed using a binomial test with a 2-year DFS < 40% as ineffective (α=10%, power=80%). Between February 2018 and March 2021, 57 patients were included and treated. Median age was 61 years, 80% male. Median number of cycles of N was 9 (from 3 to 10). The reasons for off treatment were: 60% treatment completion, 21% tumor progression, 12% toxicity, 7% Others. 2-year DFS was 46.6%, 90%CI[36.1-57.5%] for the main endpoint and 2-year OS was 67.3%, 95%CI[54.2-78.2%]. Median follow-up was 48.2 months (from 5.3 to 59.6). 17 adverse events (AEs) grade ≥3 were related to N (mainly pancreatic hepatobiliary disorders, colitis, myositis andmyocarditis) and occurred in 11 pts (19%). No drug-related death occurred. Biomarkers data (CPS, Immunoscore) will be presented. N as AT after SS is well tolerated. The 2-year DFS and OS compared favorably with those from historical data of reirradiation trials. In JANORL2 trial (Radiother Oncol 2018), 2-year DFS and OS were respectively 33.4%, 95%CI [22.1-47.0%] and 54.0%, 95%CI [40.6-66.8%]. These encouraging results warrant further investigations.

Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare subtypes of kidney cancer with a poor prognosis in the metastatic setting. Beyond first-line treatment, there are no standard-of-care therapies. This retrospective study assessed the efficacy of treatments after first-line chemotherapy in 57 patients with metastatic (m) CDC (n = 35) or RMC (n = 22) treated between 2010 and 2019 at 11 French centers. The median age was 53 years; overall, 60% (n = 34) of patients were metastatic at diagnosis. After a median follow-up of 13 months, the median overall survival was 12 (95% CI, 11–16) months. All patients received first-line platinum chemotherapy ± bevacizumab, with a median time to progression of 7.27 (95% CI, 7–100 months and an objective response rate (ORR) of 39% (95% CI, 26–52%). Patients received a median of two (1–5) treatment lines. Subsequent treatments included tyrosine kinase inhibitors (n = 12), chemotherapy (n = 34), and checkpoint inhibitors (n = 20), with ORR ranging 10–15% and disease control rates ranging 24–50%. The duration of response for all treatments was ~2 months. Notably, nine patients with CDC were still alive > two years after metastatic diagnosis. Beyond first-line therapy, treatments showed very low antitumor activity in mCDC/RMC. A better understanding of the biology of those rare tumors is urgently needed in order to identify potential targets.

In 2014, the GETUG 13 trial has established the role of early intensified treatment for men with poor prognosis germ-cell tumors (GCT) and unfavorable tumor marker decline (Fizazi K, Lancet Oncol 2014). Patients with unfavorable marker decline were randomized after 1 cycle of BEP to receive either 3 additional BEP or dose-dense chemotherapy with personalized cumulative doses of bleomycin (potentially exceeding the 300 mg recommended threshold) based on serial lung function assessments. We assessed pulmonary toxicity of this strategy.

Previous studies examined the impact of ATB on immune checkpoint inhibitor efficacy across a wide range of tumors, including genitourinary neoplasms. Perturbation of the gut microbiota has been indicated as a putative mechanism to explain this influence. We aimed to assess the impact of ATB in refractory mRCC pts.

Based on a potential synergistic effect of anti–PD-L1 avelumab plus cetuximab and radiotherapy (RT), this combination was tested in a randomized phase III trial against 2 standards of care (SOC) in LA-SCCHN. The trial comprised 2 cohorts of patients (pts) fit for cisplatin (3 cycles of 100 mg/m2, Q3W) or unfit for cisplatin. The SOC was IMRT 70 Gy / 6.5 weeks with cisplatin in fit pts and with cetuximab in unfit pts (Bonner, 2006). In both cohorts, experimental arm (Exp) was 70 Gy / 6.5 weeks plus weekly cetuximab and avelumab 10 mg/kg at Day-7 and every 2 weeks during RT followed by avelumab for 12 months. The primary endpoint was progression-free survival (PFS). In Unfit pts, 115 events were needed / 277 pts to detect a HR of 0.62 (1-sided 0.05 type I error; power 80%). In Fit pts, 166 events were needed / 430 pts to detect a HR of 0.64 (2-sided 0.05 type I error; power 80%). Between 2017 and 2020, 707 pts were randomized. For cisplatin unfit pts, out of 277 pts, the number of PFS events was reached. Median age 67 years, 88% smokers, 61% oropharyngeal tumors (35% p16+), 24% stage III, 76% stage IV. Grade >= 3 AEs were 80% in both arms (p=0.91). Median follow-up was 21 months (IQR 15-28). PFS rate at 2 years (95%CI) was 44% (35%-53%) in Exp vs 31% (23%-40%) in Cetux-SOC (HR 0.85; p=0.15). Loco-regional progression at 2 years (95%CI) was 34% (26%-43%) in Exp vs 44% (35%-53%) in Cetux-SOC (HR = 0.83; p=0.34). Distant metastasis rate was lower in Exp (HR = 0.31, p=0.007). The 2-year OS rate (95%CI) was 58% (48%-67%) in Exp vs 54% in SOC (44%-64%) (HR 1.08; p-=0.69). For cisplatin fit pts, out of 430 pts, the number of PFS events was not reached. The interim analysis for futility based on 89 events in 317 first pts showed a 1-year PFS rate (95%CI) of 64% (54%-72%) in Exp vs 73% in SOC-cisplatin (65%-81%): HR 1.27 (95%CI 0.83-1.93), crossing the futility boundary. In cisplatin-Unfit pts, a favorable effect of adding avelumab to cetuximab was seen on PFS, local-regional control, distant metastases, but the primary endpoint on PFS was not met. In cisplatin-Fit pts, the futility boundary for efficacy was crossed, favoring SOC cisplatin.

Immune checkpoint inhibitors (ICI) have been approved in recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC), in 1st line or in subsequence treatment after platinum failure. However overall response rate (ORR) and median progression free survival (mPFS) were low with any predictive factors described. We describe a cohort of patients with long response to ICI (single or combination) for R/M-HNSCC.

Beta-blockers have been associated with improved survival and immune checkpoint inhibitors (ICI) efficacy in cancer patients. We aimed to evaluate whether BB has an impact on outcomes of mRCC patients treated with N. The multicentric and prospective study NIVOREN GETUG AFU 26 evaluated the safety and efficacy of N in mRCC patients after failure of 1 or 2 tyrosine kinase inhibitors. Patients were treated between February 2016 and June 2017. Patients who were treated with BB at N start were compared with those who did not. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and toxicities were assessed. Multivariate Cox analysis was used to adjust for age and BMI. Overall, 698 patients were enrolled. One hundred and fifty-seven (22.5%) patients were treated with BB. From these, 143 (91.1%) received β1-selective blocker and 14 (8.9%) received pan β-blocker. Clinical characteristics were similar between both groups, except for median age and BMI (Table). Median OS was 22.8 (95%CI: 17.5-28.7; 82 events) months for BB users versus 24.1 (95%CI: 20.7-27.8; 263 events) months in non-users [HR 1.07 (0.83-1.37), p=0.6004]. Median PFS was 3.8 (95%CI: 2.8-5.2; 133 events) months in BB users versus 3.1 (95%CI: 2.8-4.4; 455 events) months in non-users [HR 0.99 (0.82-1.20), p=0.9409]. In multivariate analysis, both endpoints were not associated to BB at nivolumab start. The groups did not differ for ORR: 20.0% for BB users versus 20.1% for BB non-users (p=0.975). Toxicity was similar between groups.Table: 697PPatient characteristicsALL (n=698)BB (n=157)No BB (n=541)Age(year)Median (range)64 (22; 90)68 (33; 86)62 (22; 90)Gender–no(%)Male540 (77)123 (78)417 (77)BMI–no(%)<25 kg/m2333 (49)62 (40)271 (51)≥25 kg/m2353 (51)94 (60)259 (49)Missing12111Histology–no(%)Clear Cell695 (100)157 (100)538 (100)Missing303IMDC score–no(%)Good126 (18)28 (18)98 (18)Intermediate391 (56)91 (58)300 (56)Poor179 (26)38 (24)141 (26)Missing202ECOG PS–no(%)≥2102 (16)23 (15)79 (15)Missing36729Previous lines–no(%)1-2541 (78)119 (76)422 (78)≥3157 (22)38 (24)119 (22) Open table in a new tab There is no impact of BB in mRCC patients treated with N in our study.

4560 Background: In the multicenter, open-label, randomized, phase 3 CLEAR study, LEN + PEMBRO had significant PFS and OS benefits, and improved ORR vs SUN in first-line advanced RCC. Herein, we explore efficacy according to selected subgroups and the association between pts’ depth of response and OS. Methods: Pts in the CLEAR study were randomly assigned 1:1:1 to 1 of 3 treatment arms: LEN 20 mg orally QD + PEMBRO 200 mg IV Q3W; LEN 18 mg + everolimus 5 mg orally QD; or SUN 50 mg orally QD (4 weeks on/2 weeks off). We report PFS, OS, and ORR based on IMDC risk group (favorable and intermediate/poor) and presence of a target kidney lesion at baseline (post hoc analysis). Post hoc 6-month landmark analyses assessed the association between tumor shrinkage and OS. Pts who were alive at 6 months were grouped based on maximum tumor shrinkage from baseline or confirmed complete response (CR) up to 6 months. Tumor assessments were performed by independent review committee per RECIST v1.1. Odds ratios were calculated using the Cochran-Mantel-Haenszel method; HRs were based on stratified Cox proportional hazards model. Results: Among 1069 pts randomized in the CLEAR study, 355 were assigned to LEN + PEMBRO and 357 to SUN. Median follow-up was 27 months for the LEN + PEMBRO group and 26 months for the SUN group. PFS favored LEN + PEMBRO (median 22.1 months, n=243) vs SUN (median 5.9 months, n=229) in the IMDC-intermediate/poor subgroup (HR 0.36 [95% CI 0.28-0.47]); and in the IMDC-favorable subgroup (median 28.1 months, n=110 vs median 12.9 months, n=124; HR 0.41 [95% CI 0.28-0.62]). OS favored LEN + PEMBRO vs SUN in the IMDC-intermediate/poor subgroup (HR 0.58 [95% CI 0.42-0.80]); few events were observed in the IMDC-favorable subgroup thus, it was inadequate to evaluate OS. ORR favored LEN + PEMBRO vs SUN in the IMDC-intermediate/poor subgroup (72.4% vs 28.8%; odds ratio 6.60 [95% CI 4.39-9.90]) and the IMDC-favorable subgroup (68.2% vs 50.8%; odds ratio 2.00 [95% CI 1.17-3.42]). In pts with target kidney lesions, PFS, OS, and ORR were improved with LEN+PEMBRO vs SUN (table). The 6-month landmark analysis in the LEN + PEMBRO group showed that the OS rate at 24 months was 100% (95% CI not estimable [NE]-NE) for pts with confirmed CR per RECIST v1.1 and 91.7% (95% CI 53.9-98.8) both for pts with >75% to <100% target-lesion reduction and pts with 100% target-lesion reduction. Conclusions: In pts with target kidney lesions, LEN + PEMBRO conferred survival benefits vs SUN similar to benefits observed in the overall population. Overall, pts treated with LEN + PEMBRO who had greater than 75% reduction in target lesions had similar OS rates to pts with CR. Clinical trial information: NCT02811861. [Table: see text]

Renal medullary carcinoma (RMC) and collecting duct carcinoma (CDC) account for < 3% of kidney cancers. They share clinico-pathologic features and have a poor prognosis. First-line metastatic treatment is based on a gemcitabine + platinum (GC) regimen. Retrospective data suggest progression-free survival (PFS) increased with the addition of bevacizumab (bev). We prospectively assessed the safety and efficacy of GC + bev in metastatic RMC/CDC. UNICANCER designed a national phase 2 open-label trial in 18 centres in France. Patients (pts) with metastatic RMC/CDC and no prior systemic treatment were eligible. A central pathological review was performed before starting treatment. Pts received bev 15 mg/kg on day 1 (D1) + gemcitabine 1.250 mg/m2 on D1, D8 + cisplatin 70 mg/m2 or carboplatin AUC5 on D1 every 3 weeks up to 6 cycles. Pts with no progressive disease after 6 cycles continued bev alone until progression or toxicity. The co-primary endpoints were: objective response rate (ORR) and PFS at 6 months (ORR-6; PFS-6). The rule to declare the treatment effective was at least 15 pts with a positive ORR-6 or 25 pts with positive PFS-6. From Feb 2015 to Jan 2019, 34 pts were enrolled (3 with RMC and 26 with CDC, 5 unknown). At interim analysis, the IDMC closed the trial for toxicity. After a 25-month median follow-up, the ORR-6 was 29% (10/34) and the PFS-6 was 41% (14/34). The overall ORR was 39% (1 complete response, 12 partial responses). The median overall survival was 11 months (7-15). Overall, 25 pts (73%) completed the 6 cycles. Seven pts discontinued bev because of hypertension (3), proteinuria (3), or colonic perforation (1). Five pts stopped chemotherapy due to haematological (3 with carboplatin) or renal toxicity (2 with cisplatin). Grade 3–4 toxicities were reported in 28/34 pts (82%); the most common toxicities were haematological (20/34) and hypertension (5/34). Two pts had grade 5 toxicity: a subdural hematoma after C1 and encephalopathy after 5 months of treatment. The study did not meet its co-primary endpoints. Based on the observed toxicity of the combination, a GC regimen without the addition of bev remains the standard treatment for patients with RMC/CDC.

This was a double-blind, randomized phase 2 study of 96 patients with poor prognosis locally advanced, squamous cell carcinoma of the head and neck (LA-SCCHN). Previously reported data showed significant improvements of xevinapant (Debio 1143) versus placebo in addition to chemoradiation (CRT) for the primary endpoint of locoregional control (LRC) rate at 18 months, and demonstrated that addition of Debio 1143 was feasible, safe and did not compromise backbone therapy. Here we report up-dated data on PFS and overall survival (OS). Patients, stratified by node involvement, tumor localization and HPV-16 status, were randomized (1:1) to receive Debio 1143 or matching placebo at 200 mg/day, oral once daily D1–14 q3w (3 cycles) when added to standard high-dose cisplatin CRT. PFS and OS were analyzed using a Cox model in the intention-to-treat population. Median and survival rates at 36 months were estimated by the Kaplan-Meier method. As of 21 Jul 2020, the median follow-up was 33 months. Debio 1143 combined with CRT showed a statistically significant improvement in OS vs placebo by reducing the risk of mortality by 51% (HR=0.49, [95%CI: 0.26-0.92], P=0.0261). The 3 years OS rate was 66% (95% CI: 49–78) in the Debio 1143 arm versus 51% (95% CI: 34–65) in the placebo arm; the median OS is not reached with Debio 1143 vs. 36.1 months with placebo (95%CI: 21.8-46.7). Statistically significant improvement in PFS was demonstrated, reducing the risk of disease progression or death by 66% (HR=0.34 [95%CI, 0.17-0.68], p=0.0023) and improving probability of PFS at 36 months to 72% in the Debio 1143 arm compared to 36% in the placebo arm. The predictable and manageable safety profile observed with Debio 1143 + CRT after 2 years remained unchanged after 3 years. These results with extended follow-up confirm those previously reported, showing now in addition a statistically and clinically significant OS benefit by adding Debio 1143 to standard CRT. The confirmatory phase III Trilynx study (EudraCT Number: 2020-000377-25) is ongoing.

Hotspot edPOLE mutations (mut) generate proofreading defects and hypermutated genomic profiles. While rare in the advanced setting, most edPOLE mut pathogenicity and derived sensitivity to anti-PD-1 (aPD1) agents remains unclear. We aimed to investigate the efficacy of nivolumab in MMRp tumours with edPOLE mut.

Immune rejection of tumors is contingent to the development of a specific immune response and presence of a favorable TME. We aimed to evaluate the immune priming effect of TG4001, an HPV E6/E7 vaccine based on a recombinant Modified Vaccinia Ankara combined with avelumab, an anti-PD-L1 monoclonal antibody, in HPV+ cancers (NCT03260023). 34 patients (pts) with recurrent/ metastatic HPV16+ anal (15), oropharyngeal (8), cervical (6) or vulvar/vaginal (5) cancer were administered 5·107 pfu SC weekly for 6 weeks (wks), every 2 wks up to month 6, and then every 12 wks in combination with avelumab IV at 10mg/kg every 2 wks. Tissue and PBMC samples were collected at baseline and day (D) 43. T cell responses against HPV antigens were measured using ex-vivo IFNγ-ELISPOT on PBMCs; PD-L1 expression and CD3 and CD8+infiltrate were evaluated by immunostaining of tumor, and changes in gene expression were measured using nanostring. 7 pts achieved partial response and 1 achieved complete response according to RECIST 1.1. 7/11 pts evaluable for ELISPOT developed reactive T cells against E6, E7 or both after vaccination. The patient with complete response had an intense T cell response against E6 and E7 at D43. Reanalysis of this patient after 6 months showed that the T cell response was maintained, consistent with sustained disease control. At baseline, higher level of PD-L1 expression was seen in clinical responders vs. non-responders as well as higher CD3 (median: 470 vs. 200/mm2) and CD8 cell (median: 238 vs 92 /mm2) infiltrates. Infiltrates tended to increase during treatment and, at day 43, were accompanied by strong changes of the tumor transcriptomic profile, involving increase in expression of effector T cell activation cascades such as CD3G, IL21R and IFNG (respectively, 13-fold, 17-fold and 9-fold versus baseline). The Immunosign gene signature was applied as an index of “cold” or “hot” TME profile. 57% of pts had “hot” TME profile at baseline versus 100% at D43. TG4001 and PD-L1 blockade with avelumab led to the development of specific immunity and TME transformations in HPV+ cancer pts potentially leading to clinical benefit.