Search

International audience; BACKGROUND: Recent studies suggest improvements in response to salvage chemotherapy (CT) after immune checkpoint inhibitors (ICIs) in several types of cancer. Our objective was to assess the efficacy of chemotherapy re-challenge after ICI, compared with second-line chemotherapy without previous ICI in patients with locally advanced or metastatic urothelial carcinoma (la/mUC). METHODS: In this multicentre retrospective study, we included all patients with la/mUC initiating second or third-line chemotherapy from January 2015 to June 2020. We compared patients treated with second-line chemotherapy without previous ICI (CT2) and patients treated with third-line chemotherapy after ICI (CT3). The primary end-point was objective response rate (ORR) in CT3 compared with CT2. Secondary end-points included progression-free survival (PFS) and toxicities. RESULTS: Overall, 553 patients were included. ORRs were 31.0% (95% CI, 26.5 to 35.5) and 29.2% (95% CI, 21.9 to 36.6), respectively, in CT2 and CT3, with no statistically significant differences (P = 0.62). In subgroup analyses, no differences in ORR were observed by Bellmunt risk group, type of chemotherapy (platinum or taxanes), duration of response to first-platinum-based chemotherapy (< or ≥ 12 months) or FGFR-status. Median PFS was 4.6 months (95% CI, 3.9 to 5.1) and 4.9 months (95% CI, 4.1 to 5.5) in CT2 and CT3, respectively, and grade 3-4 hematologic toxicity occurred in 35.0% and 22.4% of patients. CONCLUSION: This large multicentre retrospective study provides clinically relevant real-world data. Chemotherapy re-challenge after ICI in la/mUC achieves ORR and PFS comparable with those obtained in CT2 with an acceptable safety profile. These updated results offer more promising outcomes than historically reported with second-line chemotherapy data.

With the approval of new therapies targeting the PI3K pathway, the detection of PIK3CA mutations has become a key factor in treatment management for HR+/HER2− metastatic breast cancer (MBC). We developed multiplex digital PCR (dPCR) assays to detect and quantify PIK3CA mutations. A first screening assay allows the detection of 21 mutations, with a drop-off system targeting the 542–546 hotspot mutations combined with the simultaneous detection of N345K, C420R, H1047L and H1047R mutations. In the case of a positive result, a sequential strategy based on other assays that we have developped allows for precise mutation identification. Clinical validity was determined by analyzing plasma circulating free DNA (cfDNA) from 213 HR+/HER2− MBC samples, as well as DNA extracted from 97 available matched tumors from 89 patients. Our assays have shown reliable specificity, accuracy and reproducibility, with limits of blank of three and four droplets for the screening assay. Sixty-eight patients (32%) had at least one PIK3CA mutation detectable in their plasma, and we obtained 83.1% agreement between the cfDNA analysis and the corresponding tumors. The high sensitivity and robustness of these new dPCR assays make them well-suited for rapid and cost-effective detection of PIK3CA mutations in the plasma of MBC patients.

Aims: In HER2CLIMB, tucatinib significantly improved progression-free and overall survival in patients with human epidermal growth factor receptor 2–positive (HER2+) metastatic breast cancer. We evaluated the impact of tucatinib on health-related quality of life (HR-QoL) in HER2CLIMB. Methods: Patients were randomised 2:1 to tucatinib or placebo combined with trastuzumab and capecitabine. Starting with protocol version 7, the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire and EQ visual analogue scale (VAS) were administered at day 1 of cycle 1, every two cycles during cycles 3–9, every three cycles during cycle 12 and thereafter and at each patient's 30-day follow-up visit. Results: Among 364 patients eligible for HR-QoL assessment, 331 (91%) completed ≥1 assessment. EQ-VAS scores were similar for both arms at baseline and maintained throughout treatment. EQ-5D-5L scores were similar between the treatment arms, stable throughout therapy and worsened after discontinuing treatment. Risk of meaningful deterioration (≥7 points) on EQ-VAS was reduced 19% in the tucatinib vs. placebo arm (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.55, 1.18); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.8 months (4.3, -) in the placebo arm. Among patients with brain metastases (n = 164), risk of meaningful deterioration on EQ-VAS was reduced 49% in the tucatinib arm (HR: 0.51; 95% CI: 0.28, 0.93); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.5 months (4.2, -) in the placebo arm. Conclusions: HR-QoL was preserved for patients with HER2+ metastatic breast cancer who were treated with tucatinib added to trastuzumab and capecitabine and maintained longer with tucatinib therapy than without it among those with brain metastases. Clinical Trial Registration: NCT02614794

Purpose: Genomic signatures, such as EndoPredict®, may help clinicians to decide which adjuvant treatment is the most appropriate. Methods: We propose the EndoPredict® assay for unclear cases of adjuvant treatment in patients treated in our comprehensive cancer center. We prospectively and retrospectively report the decision of adjuvant treatment before and after the EndoPredict® assay, respectively, compared to the PREDICT’s tool scores. Results: From November 2016 to March 2019, 159 breast cancer tumors were analyzed and presented before and after the EndoPredict® assay. Before the EndoPredict® results, clinicians recommended chemotherapy for 57 patients (57/159, 36%). A total of 108 patients (108/159, 68%) were classified as EPclin high-risk score. There was only a slight agreement between clinicians’ decisions and EPclin risk score. The EPclin score led to 37% changes in treatment (59/159); chemotherapy was favored in 80% of cases (47/59). The PREDICT tool recommended chemotherapy for 16 high-risk patients (16/159, 10%). Conclusion: Although genomic tests were developed in order to de-escalate adjuvant treatment, in our comprehensive cancer center the use of the EndoPredict® assay led to an increase in prescribed chemotherapy.

Purpose Fumarate hydratase–deficient (FHdef) renal cell carcinoma (RCC) is a rare entity associated with the hereditary leiomyomatosis and RCC syndrome with no standard therapy approved. The aim of this retrospective study was to evaluate the efficacy of different systemic treatments in this population. Methods We performed a multicentre retrospective analysis of Fhdef RCC patients to determine the response to systemic treatments. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and overall survival (OS). The two latter were estimated using the Kaplan–Meier method. Results Twenty-four Fhdef RCC patients were identified, and 21 under systemic therapy were included in the analysis: ten received cabozantinib, 14 received sunitinib, nine received “other antiangiogenics” (sorafenib, pazopanib, and axitinib), three received erlotinib-bevacizumab (E-B), three received mTOR inhibitors, and 11 received immune checkpoint blockers (ICBs). ORR for treatments were 50% for cabozantinib, 43% for sunitinib, 63% for “other antiangiogenics,” and 30% for E-B, whereas ORR was 0% for mTOR inhibitors and 18% for ICBs. The median TTF (mTTF) was significantly higher with antiangiogenics (11.6 months) than with mTOR inhibitors (4.4 months) or ICBs (2.7 months). In the first-line setting, antiangiogenics presented a higher ORR compared with nivolumab-ipilimumab (64% versus 25%) and a significantly superior mTTF (11.0 months vs 2.5 months; p = 0.0027). The median OS from the start of the first systemic treatment was 44.0 months (95% confidence interval: 13.0–95.0). Conclusions We report the first European retrospective study of Fhdef RCC patients treated with systemic therapy with a remarkably long median OS of 44.0 months. Our results suggest that antiangiogenics may be superior to ICB/mTOR inhibitors in this population.

430 Background: Primary urethral cancer (PUC) is a rare and heterogeneous malignancy. Due to its scarcity, little data are available on the optimal treatment sequence and survival, especially in metastatic patients. Methods: Data from patients diagnosed with a PUC between 01/01/2000 and 12/31/2018 were retrospectively collected from nine French referral centers. Survival rate were estimated with the Kaplan-Meier method and prognostic factors were analyzed using the Cox proportional hazards model and the log-rank test. In order to increase the statistical power of survival analysis in the metastatic stage, patients with synchronous and metachronous metastatic disease were pooled. Results: We identified 44 (62%) males and 27 (38%) females with a PUC. The most frequent histological types were urothelial carcinomas (40.0%), squamous cell carcinomas (34.3%) and adenocarcinomas (14.3%). Twenty-five (35.2%) patients were diagnosed at a localized stage (≤ T2, N0, M0); 35 (49.3%) at a locally advanced stage (≥ T3 or ≥ N1, M0) and 11 (15.5%) at a distant stage (M1). Twenty-seven patients had a metachronous metastatic cancer. Multimodality therapy was used in 24.0% and 57.1% of the patients with a localized and locally advanced disease, respectively. In the entire cohort, median overall survival (OS) was 52.5 months (IC95% 32.2 – 64.1) and stage at diagnosis was a predictor of OS (p < 0.0001). For the 60 patients with a non-metastatic disease, 39 (65%) had a recurrence or were dead and the median disease-free survival (DFS) was 21.2 months (IC95% 16.8 – 34.5). Nodal involvement was the only factor associated with DFS (HR: 2.03, p = 0.0390). Multimodal treatment compared with unimodal treatment was not significantly associated with DFS (HR: 1.22, p = 0.5419). Regarding survival of the 38 metastatic patients, the median OS was 15.2 months (IC95% 8.2 – 23.5) and the median progression-free survival was 6.4 months (IC95% 4.4 – 9.8). Conclusions: This retrospective study showed an important heterogeneity in terms of histology, stage at diagnosis, and treatment of PUC. In this cohort, the multimodal approach did not show any improvement in survival of non-metastatic patients. This study is one of the few to describe the survival in metastatic patients.

492 Background: Immune checkpoints inhibitors (ICIs) have recently changed therapeutic landscape of la/mUC. Recent studies suggested an improvement of response to salvage chemotherapy (CT) after ICIs in several cancer types including urothelial carcinoma. We assumed that efficacy of CT rechallenge after ICIs may be improved compared to second-line CT without previous ICIs in patients (pts) with la/mUC. Methods: CIMUC is a French multicentric retrospective study including all pts with la/mUC initiating second or third-line CT from January 1st 2015 to June 30th 2020. Two groups of pts were defined: pts in group 1 (G1) were treated with a second-line CT without previous ICIs; pts in group 2 (G2) were treated with third line CT after ICIs. Primary endpoint was objective response rate (ORR: proportion of patients with complete or partial response, according to RECIST 1.1 criteria) in G2 versus G1. Secondary endpoints were progression-free survival (PFS), defined as time from initiation of second or third-line CT to disease progression or death from any cause, and toxicities. This study is supported by the French Genito Urinary Group (GETUG). Results: 553 pts were included. Baseline characteristics of the 2 groups are summarized in the Table. ORRs were 31% (95%CI [26.5-35.5]) and 29.2% (95%CI [21.9-36.6]) respectively in G1 and G2, without statistically significant difference (p=0.617), even after adjustment for Bellmunt risk factors (p=0.3214). In subgroups analysis, no difference in ORR was observed by type of CT (platinum or taxanes), duration of response (DOR) to first-platinum-based CT (< 12 months or ≥ 12 months) and FGFR-status. We did not identify any predictive factor of OR in G2 in multivariate analysis. Median PFS were 4.6 months (95%CI [3.88; 5.06]) and 4.86 months (95%CI [4.11; 5.45]), respectively in G1 and G2. Grade 3/4 hematologic toxicity occurred in 35% and 22.4%, respectively in G1 and G2. Conclusions: While ORR was not superior in G2 versus G1, pts derive comparable benefit in a further line of treatment (G2) in terms of ORR and PFS. Despite limits inherent to any retrospective study, CIMUC represents one of the largest retrospective studies in this setting.[Table: see text]

Background Patients (pts) with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (MBC) who have brain metastases (BM) have limited treatment options and lower health-related quality of life (HRQoL) compared with pts without BM (Hurvitz 2019). HER2CLIMB is a randomized trial (2:1) of tucatinib vs. placebo in combination with trastuzumab and capecitabine in pts with HER2+ MBC that included pts with stable and active brain metastases (NCT02614794). In HER2CLIMB, the addition of tucatinib to trastuzumab + capecitabine demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) in pts with HER2+ MBC and in those with stable and active BM, with importantly, a tolerable and manageable safety profile (Murthy 2020). An evaluation of the impact of tucatinib on HRQoL in pts with stable and active BM is presented here. Methods HRQoL data were available from 330 of 612 pts, including 163 pts with BMs. HRQoL was assessed using the EQ-5D-5L tool which includes a visual analog scale (EQ-VAS) and a descriptive system (EQ-5D) comprising 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Data were collected at Cycle 1 Day 1, Cycles 3-9 (every 2 cycles; 21-day cycles), Cycle 12 and beyond (every 3 cycles), and at the 30-day follow-up. The EQ-5D-5L scores were summarized by cycle for each treatment arm. Time to deterioration, defined as a >7-point change from baseline on the EQ-VAS, was estimated by the Kaplan-Meier approach. The median time to deterioration (and 95% CIs) were computed for each arm. Results In total, 163 pts with stable and active BM were included in this HRQoL analysis, 107 pts on the tucatinib arm and 56 pts on the placebo arm. Compared to the placebo arm, pts on the tucatinib arm had an approximately 49% reduction in the risk of deterioration (hazard ratio: 0.51; 95% CI: 0.28, 0.93); the median time to deterioration has not been reached in the tucatinib arm with available follow-up and was 5.5 months (95% CI; 4.2, -) in the placebo arm. Decline in all domains of the EQ-5D-5L and the EQ-VAS scores were seen once pts discontinued therapy, particularly on the ‘usual activities’ domain. Additional available QoL data will be presented. Conclusions Pts with MBC and BM treated with tucatinib in combination with trastuzumab + capecitabine demonstrated significantly longer and clinically meaningful time to deterioration of HRQoL. HRQoL was maintained throughout the treatment course, allowing them to receive full benefit of the therapeutic approach and resulting in statistically significant and clinically meaningful improvement in OS. References Hurvitz SA, O’Shaugnessy J, Mason G, et al. Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs. Clin Cancer Res. 2019;25(8):2433-2441.Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020;382(7):597-609. Citation Format: Andrew Wardley, Volkmar Mueller, Elisavet Paplomata, Laurence Crouzet, Nayyer Iqbal, Sramila Aithal, Margaret Block, Søren Cold, Marie-Agnes By, Olwen Hahn, Teja Poosarla, Erica Stringer-Reasor, Marco Colleoni, David Cameron, Giuseppe Curigliano, Kendra DeBusk, Muriel Siadak, Jorge Ramos, Xuebei An, Karen Gelmon. Impact of tucatinib on health-related quality of life in patients with HER2+ metastatic breast cancer with stable and active brain metastases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-04.

Managing endocrine resistance and resistance to endocrine therapy for ER+ HER2- breast cancer with the CDK 4/6 inhibitors in the metastatic setting. New antibodies drug conjugates for HER2+ and TNBC. Targeting DNA damage and synthetic lethality strategies with PARP inhibitors for breast cancer patients harboring BRCA mutation. Immunotherapies in 1st line metastatic setting of TNBC.

Resume Introduction Le sorafenib est le standard de traitement du carcinome hepatocellulaire (CHC) avance. Ce medicament est administre par voie orale et associee a une toxicite significative. Nous avons cherche a ameliorer le suivi par l’oncologue medical (OM) en impliquant des infirmieres cliniciennes dediees (ID). Patients et methodes Depuis janvier 2011, les patients sont vus par les ID pendant une heure avant le debut du traitement, puis suivis toutes les semaines par des appels telephoniques. Dans cette etude, nous avons compare de maniere retrospective les patients suivis par les ID avec ceux suivis en OM ou en essai therapeutique. Resultats Depuis 2008, 129 patients ont ete traites dans notre institution par sorafenib pour CHC, 31 (24 %) avec suivi par ID, 22 (17 %) dans un essai et 76 (59 %) en OM. Les patients suivis par les ID ont necessite moins de reduction de dose (39 % vs 61 % en OM, p = 0,04). Le temps median jusqu’a la premiere diminution de dose etait plus court (25 jours vs 45 jours, p = 0,04). Il y avait une tendance a moins de pause de traitement (19 % vs 34 %, p = 0,13) et vers moins d’arret du traitement pour toxicite (26 % vs 36 %, p = 0,33). Cependant, il n’y avait pas de difference dans la survenue de toxicite severe (48 % pour ID vs 42 % pour OM, p = 0,73). Conclusion Bien que retrospective, cette analyse suggere un interet du suivi par ID, avec une meilleure gestion des effets indesirables qui conduit a une reaction plus rapide et moins de reductions posologiques.

420 Background: Only scarce data exist on the management of residual masses in men who have received two lines of chemotherapy for advanced seminoma. Due to the lack of data, the role of PET scanning, surgery and other additional treatments is controversial in these men. Methods: Data from men with pure seminoma and residual masses after salvage chemotherapy were retrospectively collected from 10 high-volume centers in 3 European countries. We analyzed the clinical management of residual masses (imaging, surgery, pathological data, and additional treatment modalities) and long-term outcomes. Residual mass was defined as a lesion of ≥1 cm after two lines of platin-based chemotherapy. Results: To date, data from 48 patients (pts) with non-progressing residual masses after second line (salvage) chemotherapy have been collected and are included in this analysis. Median age at diagnosis was 36 years (range 31; 42). A post-chemotherapy PET-FDG was performed in 32 (67%) pts. Surgery was performed in 20/48 (41%) pts irrespectively of FDG uptake (no, n=8; yes, n=5). Complete necrosis was found in 16 (80%), viable seminoma in 3 (15%), and teratoma in 1 pt, respectively. All pts with a negative PET (PET-) who underwent surgery (8/8) had complete necrosis. 5/11 pts with a positive PET (PET+) underwent surgery: 3 had a complete necrosis while 2 had viable seminoma. Among those with a PET+, 3 pts (28%) experienced either viable seminoma in residual masses or a subsequent relapse. The absence of FDG uptake correlated with absence of viable cancer (p=0.04). A second relapse occurred in 5/48 pts (10%). Only 2/20 pts who had residual masses resected post 1st salvage chemotherapy subsequently relapsed (one had viable seminoma in the residuals). At a median follow up of 4 years (IC95% [3.5-5.5]), 41/48 pts (87%) were alive. 7/48 patients died of cancer progression. Conclusions: Most men with residual masses after 1st salvage chemotherapy for advanced seminoma may achieve a cure. Pending validation with more pts in this rare situation, PET-FDG may help guide who should be selected for post-chemotherapy resection. Updated results will be presented at the congress.

International audience; PURPOSE: Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). The peak incidence of HCC is around 70 years. We aimed to evaluate safety and efficacy of sorafenib in the elderly population. METHODS: We retrospectively reviewed data from patients treated with sorafenib for HCC at our institution. We compared safety and efficacy data across different age groups. RESULTS: Since 2005, 129 patients were treated, 78 (60.5 %) were \textless70 years old and 51 (39.5 %) were ≥70. The frequency of dose reduction was similar between the two groups (48.7 vs. 58.8 %), as was the occurrence of severe toxicities (41.0 vs. 51.0 %) and hospitalization due to toxicity (9.0 vs. 13.7 %). However, asthenia and bleeding were more frequent in the elderly. The higher frequency of bleeding was explained by concomitant antiplatelet treatments, and major asthenia was frequent in PS1 elderly patients. There was a trend toward less frequent interruption of treatment in the younger group (25.6 vs. 39.2 %) and significantly less frequent definitive discontinuation of treatment due to toxicity (24.4 vs. 45.1 %). Median progression-free survival was 5.6 months in both age groups, while median overall survival was 9.6 months in the younger age group and 12.6 months in the older age group. CONCLUSION: Sorafenib showed similar results in terms of safety and efficacy in the elderly and younger HCC populations. Careful baseline evaluation is needed for patient's selection in the elderly population, including discussion about antiplatelet therapy discontinuation and caution in PS1 patients, as well as active management of toxicity.

11053 Background: Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor and in most of cases, is characterized by an inactivation of the tumor suppressor gene VHL (Von Hippel-Lindau). This...