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TPS11585 Background: Primary metastatic osteosarcoma (OS) patients are treated with a curative intent following the same principles of non-metastatic OS, while the treatment of recurrent OS is primarily surgical in the case of isolated lung metastases. When complete removal of all metastases cannot be achieved, the prognosis remains poor, with a median Progression-Free Survival (PFS) between 3 to 8 months, and therefore there is a clinical need to reduce the risk of progression after the initial treatment sequence. The REGOBONE study reported a significant PFS benefit of regorafenib (REG) compared to placebo (in osteosarcomas: median PFS: 16.4 versus 4.1 weeks) and a manageable safety profile in patients with histologically confirmed HGBS (i.e., osteosarcoma or other bone sarcomas with the exception of Ewing sarcomas, chondrosarcoma and chordoma). Methods: This multicenter trial is ongoing to study the efficacy and safety of maintenance REG in pts > = 16 years old with HGBS, without complete remission but with no progressive disease after standard treatment, either at diagnosis or at relapse. Sixty pts will be randomly allocated in a 1:1 ratio to receive either oral REG at a daily dose of 120mg or its matching placebo, continuously for a maximum of 12 months. Randomization is stratified according to the setting of the disease: initial diagnosis versus relapse. The primary objective is to compare the efficacy (PFS) between the 2 arms. The expected 4-month PFS rates are 30% in the control arm and 60% in the REGO arm (HR = 0.42). Fifty-two events will provide 87% power to show significant improvement in PFS, using a 2-sided log-rank test at a 5% level. Secondary endpoints include Overall Response Rate (ORR), Disease Control Rate (DCR), Time to Treatment Failure (TTF), Overall Survival (OS), Quality of Life (QoL), and safety profile. Radiological endpoints will be evaluated using the RECIST 1.1 with tumor assessments every 2 months (first 6 months) and then every 3 months. Translational objectives will identify predictive biomarkers for efficacy of REG as maintenance therapy. Pts of the control arm who experience disease progression may switch to receive open label REG. As of Feb 1st, 2022, 3 patients have been randomized. 14 sites of the French Sarcoma Group will participate. An amendment is being implemented to lower the age limit (12 years old) and to expand tumor types to other HGBS (Ewing sarcomas, chondrosarcomas, Undifferentiated Pleomorphic Sarcomas, Leiomyosarcomas and angiosarcomas). Clinical trial information: NCT04698785.

5560 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial, maintenance olaparib + bevacizumab (bev) provided a significant progression-free survival (PFS) benefit vs placebo (pbo) + bev in patients (pts) with newly diagnosed advanced ovarian cancer in response to platinum-based chemotherapy. Subgroup analyses revealed a substantial PFS benefit in homologous recombination deficiency (HRD)-positive (including BRCA1/2 mutation) pts, leading to US/EU labels for this combination. Preliminary analyses reported that olaparib did not alter global health-related quality of life (G-HQoL; Ray-Coquard I et al. NEJM 2019). We analyzed HQoL by domains and molecular subgroups and explored the impact of disease progression (DP) on HQoL in the 1L setting. Methods: Eligible pts with newly diagnosed advanced (FIGO stage III–IV) HGOC were randomized 2:1 to maintenance olaparib + bev or pbo + bev. Pts completed European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 HQoL questionnaires at baseline and every 12 weeks for 2 years’ follow-up, irrespective of DP. The minimal important difference for clinically relevant change was fixed at 10 points. Longitudinal data were analyzed by mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD). Analyses were in the intent-to-treat population and HRD-positive subgroup. HQoL analyses at DP (± 60 days) were explored. Results: 806 pts were randomized to olaparib + bev (n=537) or pbo + bev (n=269). 465 pts had DP over 2 years’ follow-up. Compliance to HQoL questionnaires was high at baseline (95%) and over time (>70%). MMRM models by HQoL domain did not reveal a clinically relevant difference between treatment arms over time. TUDD of G-HQoL did not differ between arms (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.72–1.07). In the HRD-positive subgroup (n=372), we observed no difference by HQoL domain between treatment arms. Interestingly, TUDD of G-HQoL was statistically significantly in favor of olaparib + bev compared with pbo + bev (HR 0.70, 95% CI 0.52–0.93). We also observed a clinically significant deterioration in emotional (mean change −12.30 points, 95% CI −16.46 to −8.13) and social (−11.17 points, 95% CI −16.21 to −6.12) functioning in both treatment arms at DP, among 103 pts with HQoL questionnaires at DP. Conclusions: The substantial PFS benefit provided by maintenance olaparib + bev in the newly diagnosed setting was achieved without detrimental effect on HQoL domains, even with longer TUDD of G-HQoL in the HRD-positive subgroup. Use of an effective maintenance therapy (ie one with a significant PFS benefit) in HGOC patients in the 1L setting is likely to delay the clinically significant deterioration in emotional and social functioning we identified in patients at DP across PAOLA-1 treatments arms. Clinical trial information: NCT02477644.

5562 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644), maintenance olaparib plus bevacizumab (bev) provided a significant progression-free survival (PFS) benefit, compared with placebo plus bev, in patients (pts) with newly diagnosed advanced ovarian cancer in response after platinum-based chemotherapy (Ray-Coquard et al. NEJM 2019). A subgroup analysis revealed a substantial PFS benefit in HRD-positive (including BRCA1/BRCA2 mutation) pts (median PFS 37.2 vs 17.7 months) leading to US and EU labels for this combination. We analyzed TWiST in PAOLA-1, using several definitions of toxicity (TOX) and by molecular subgroups. Methods: Pts were randomized 2:1 to maintenance olaparib (300 mg bid) plus bev (15 mg/kg, Day 1, q3w) or placebo plus bev, stratified by first-line treatment outcome and tumor BRCAm status. TWiST is defined as PFS minus time with TOX after randomization and before disease progression or censoring for progression, and was a prespecified exploratory endpoint. Definitions of significant symptoms or TOX were explored using the following approaches: 1) all grade ≥2 adverse events (AEs); and 2) all grade ≥2 AEs selected to be correlated to olaparib (fatigue, nausea, vomiting, and anemia). Area under PFS curve was split into TOX:TWIST ratio and compared between the two arms. Results: Between May 7, 2015 and August 31, 2017, 806 eligible pts were randomly assigned to olaparib plus bev (n = 537) or placebo plus bev (n = 269), with a median duration of treatment with olaparib of 17.3 months (range 0.03–33.0) for olaparib plus bev arm and 15.6 months (range 0.07–26.2) for placebo plus bev at data cutoff for primary endpoint analysis. In the Intent-to-treat population, median duration of TWiST for all grade ≥2 AEs for olaparib plus bev vs placebo plus bev arms was 14.1 months (95% confidence interval [CI] 12.5–16.1) vs 7.7 months (95% CI 5.9–9.1), respectively; and 21.9 months (95% CI 20.2–22.5) vs 16.6 months (95% CI 14.6–18.0) considering only grade ≥2 AEs linked to olaparib. The difference was particularly significant within the HRD-positive subgroup where median duration of TWiST was 24.4 months (95% CI 19.3–not evaluable [NE]) vs 7.4 months (5.8–11.2) for TOX linked to all grade ≥2 AEs, and 36.6 months (95% CI 31.9–NE) vs 17.4 months (15.1–19.4) linked to olaparib AEs only for the olaparib plus bev and placebo plus bev arms, respectively. Conclusions: The substantial PFS benefit provided by maintenance olaparib plus bev vs placebo plus bev in pts with newly diagnosed advanced ovarian cancer was supported by significant TWiST benefit. TWiST analyses, including all grade ≥2 symptoms or toxicity related to treatment, confirmed the clinically meaningful benefit from the combination, notably in the HRD-positive subgroup. Clinical trial information: NCT02477644.

5514 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644), the addition of maintenance olaparib to bev in pts with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in a significant PFS benefit, particularly in HRD-positive (HRD+) pts (hazard ratio [HR] 0.33; 95% CI 0.25–0.45) (Ray-Coquard et al. NEJM 2019). We explored efficacy in HRD+ pts by disease stage. Methods: Pts with newly diagnosed, FIGO stage III–IV HGOC in response after platinum-based chemotherapy + bev received bev (15 mg/kg q3w for 15 months [mo]) + either olaparib (300 mg bid for 24 mo) or placebo (pbo). This exploratory analysis evaluated PFS (data cut-off [DCO]: Mar 22 2019) and PFS2 (DCO: Mar 22 2020) in HRD+ pts (tumor BRCA1/ BRCA2 mutation [tBRCAm] or genomic instability score [Myriad myChoice HRD Plus] ≥42) by FIGO stage. Results: 387/806 randomized pts (48%) were HRD+; 272/387 (70%) had stage III disease and 115/387 (30%) had stage IV disease. 153 (56%) HRD+ stage III pts and 61 (53%) HRD+ stage IV pts had a tBRCAm. Among HRD+ stage III pts, 172 (63%) had upfront surgery (51/172 [30%] had residual disease) and 90 (33%) had interval surgery (19/90 [21%] had residual disease); 52 (45%) HRD+ stage IV pts had upfront surgery (34/52 [65%] had residual disease) and 55 (48%) had interval surgery (18/55 [33%] had residual disease). Median follow-up for PFS and PFS2 was respectively 24.8 and 37.2 mo in HRD+ stage III pts and 24.0 and 37.0 mo in HRD+ stage IV pts. Median PFS, PFS2 and HRs are in the Table. Among HRD+ stage III pts, 36-mo PFS2 (olaparib + bev vs pbo + bev) was 74% vs 60%; among HRD+ stage IV pts, 53% vs 30%. Among HRD+ stage III pts with no residual disease after upfront surgery, HR (95% CI) for PFS was 0.15 (0.07–0.30) and for PFS2 was 0.22 (0.06–0.67). Among HRD+ stage III pts with residual disease after upfront surgery or who received neoadjuvant chemotherapy, or HRD+ stage IV pts, HR (95% CI) for PFS was 0.38 (0.27–0.53) and PFS2 was 0.68 (0.46–1.03). Conclusions: In the PAOLA-1 study, maintenance olaparib + bev provided a PFS and PFS2 benefit over pbo + bev in HRD+ pts, irrespective of FIGO stage and residual disease after upfront surgery. Clinical trial information: NCT02477644. [Table: see text]

TPS11568 Background: GastroIntestinal Stromal Tumors (GIST) are paradigmatic models of cancers with a driver mutation of an oncogene, in which imatinib is recommended as adjuvant therapy or treatment of locally advanced and metastatic forms. After failure of imatinib (either progression or toxicity), sunitinib and regorafenib are indicated as 2nd and 3rd lines, respectively. Beyond approved drugs, tyrosine kinase inhibitors (TKI) can bring clinical benefit because some clones remain sensitive to TKI. Lenvatinib is a broad spectrum TKI targeting KIT, RET, PDGFRA, VEGFR 1-3 and FGFR 1-4, that is approved in the treatment of differentiated thyroid carcinoma and metastatic renal cell carcinoma and hepatocellular carcinoma. Methods: This prospective, randomized, placebo-controlled, double-blinded, multicenter trial evaluates the efficacy and safety of Lenvatinib in adult GIST patients (pts) who failed at least to previous imatinib and sunitinib. Seventy-four pts will be randomly allocated in a 1:1 ratio to receive either oral lenvatinib, at a daily dose of 24mg, or its matching placebo, continuously, until progression of disease (PD) or unacceptable toxicity. Randomization will be stratified according to the number of different previous anticancer drugs (2 or > 2). The primary objective is to compare the Progression-free survival (PFS) between arms. The expected median PFS are 1.5 month in the control arm and 3.0 months in the experimental arm (HR = 0.5). Seventy one events will provide 90% power to show significant improvement in PFS, using a 2-sided log-rank test at a 10% level. Secondary endpoints include the overall survival, the objective response rate, the best overall response, the quality of life and the safety profile. Patients allocated in the placebo arm who experience PD (RECIST 1.1) may switch to active lenvatinib. Radiological endpoints will be evaluated using the RECIST 1.1. Translational objectives will be to identify blood and tumor parameters as predictive markers of lenvatinib efficacy. Recruitment has been activated in January 2020. Ten participating sites of the French Sarcoma Group will participate in the trial. Clinical trial information: NCT04193553 .

6039 Background: In PAOLA-1/ENGOT-ov25 (NCT02477644), adding the PARP inhibitor olaparib to maintenance bev after first-line platinum-based chemotherapy plus bev led to a statistically significant progression-free survival (PFS) benefit in pts with advanced HGOC (HR 0.59; 95% CI 0.49–0.72) (Ray-Coquard et al. 2019). Retrospective subgroup analysis in GOG-0218 (Norquist et al. 2018) suggested BRCA mutation (BRCAm) status did not significantly impact the PFS benefit provided by bev. We explored the efficacy of olaparib plus bev by BRCA1 mutation ( BRCA1m) or BRCA2 mutation ( BRCA2m) in PAOLA-1. Methods: PAOLA-1 is a randomized, double-blind, Phase III trial in pts with newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid OC, fallopian tube or primary peritoneal cancer receiving platinum-based chemotherapy plus bev then maintenance bev. Pts unrestricted by surgical outcome or BRCAm status and in response to first-line therapy were randomized to maintenance olaparib tablets (300 mg bid for up to 24 months) plus bev (15 mg/kg q3w for up to 15 months in total) or placebo plus bev, stratified by first-line treatment outcome and tumor BRCAm status. Investigator-assessed PFS (modified RECIST v1.1) by BRCAm was a predefined analysis. Results: Of 806 randomized pts, 160 (20%) had tumor BRCA1m, 76 (9%) had tumor BRCA2m and 1 (

Purpose Cross-talk between signal transduction pathways likely contributes to hormone resistance in metastatic breast cancer (mBC). Everolimus, an oral inhibitor of the mammalian target of rapamycin, has restored sensitivity in endocrine-resistance models and shown anticancer activity in early-phase mBC clinical trials. This analysis evaluated efficacy and safety of everolimus in combination with tamoxifen in patients with mBC resistant to aromatase inhibitors (AIs). Patients and Methods This open-label, phase II study randomly assigned postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative, AI-resistant mBC to tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d alone (n = 57). Randomization was stratified by primary and secondary hormone resistance. Primary end point was clinical benefit rate (CBR), defined as the percentage of all patients with a complete or partial response or stable disease at 6 months. No formal statistical comparison between groups was planned. Results The 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus and 42% (95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus everolimus, corresponding to a 46% reduction in risk of progression with the combination (hazard ratio [HR], 0.54; 95% CI, 0.36 to 0.81). Risk of death was reduced by 55% with tamoxifen plus everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 to 0.81). The main toxicities associated with tamoxifen plus everolimus were fatigue (72% v 53% with tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), and diarrhea (39% v 11%). Conclusion This study suggests that tamoxifen plus everolimus increased CBR, TTP, and overall survival compared with tamoxifen alone in postmenopausal women with AI-resistant mBC.

TPS5605 Background: Olaparib (Lynparza) is an oral PARP inhibitor indicated in the EU for the maintenance treatment of patients (pts) with platinum-sensitive relapsed BRCA-mutated high grade serous ovarian cancer (HGSOC). Bevacizumab is an anti-VEGF monoclonal antibody indicated in the EU in first line or relapse for the treatment of OC in combination with specific chemotherapeutic agents. Bevacizumab treatment is associated with increasing hypoxia-induced homologous recombination repair deficiencies in tumor cells, and is hypothesized to increase ovarian tumor sensitivity to olaparib. Methods: PAOLA-1 (ENGOT-ov25) is a randomized, placebo-controlled trial evaluating the efficacy and safety of olaparib (tablet formulation) in pts with advanced HGSOC receiving bevacizumab maintenance therapy. Eligible pts are those in complete or partial response following first-line platinum chemotherapy plus bevacizumab, and for whom bevacizumab maintenance therapy is planned. Approximately 762 European and 24 Japanese pts will be randomized 2:1 to olaparib 300 mg twice daily or placebo for up to 24 months. All pts will receive standard maintenance care of bevacizumab (15 mg/kg every three weeks) for up to 15 months. Primary objective: PFS1 according to RECIST 1.1 Secondary objectives: PFS2, OS, Safety, PRO/QoL, TFST, TSST All pts will undergo tumor BRCA testing prior to randomization. Central BRCA testing (tumor) will be performed in five screening platforms in France. Tumor BRCA test results have to be available within two months of sample provision. PFS will be evaluated using a log-rank test stratified by response to first-line treatment and BRCA mutation status. Treatment effect hazard ratio of 0.7 is expected and final PFS1 analysis will be performed after 372 events. The first pt from eight ENGOT groups plus Japan (10 participating countries) was randomized in July 2015. As of 31 January 2017, 549 pts have been randomized. The median period between the provision of a tumor sample and returned BRCA test result is 40 days. Accrual is expected to be complete before July 2017. Clinical trial information: NCT02477644.

11054 Background: Advanced SyS are rare tumors with limited curative options. FZD10 is highly expressed in SyS but not in normal adult tissue. OTSA101 is a MAb targeting FZD10, labelled with a radioisotope. Methods: We conducted a phase I, FIH study including adult pts with advanced, refractory SyS. In part 1, pts received OTSA101 labelled with In111 used as radiotracer to assess biodistribution and tumor uptake. In part 2, pts with significant tumor uptake were randomized to receive OTSA101 labelled with 370MBq of Y90 (Arm A) or 1110MBq Y90 (Arm B). Primary endpoints were occurrence of unacceptable biodistribution /lack of tumor uptake in part 1 and occurrence of related adverse events (AEs) Grade ≥ 3 during the first 8 weeks following injection of Y90OTSA101 in part 2. Responses were assessed per RECIST 1.1. Results: From January 2012 to June 2015, 20 pts (10 females, median age 43, range 21-67) with advanced SyS were enrolled. Ten pts (50%) had sufficient tumor uptake to proceed to part 2 and 8 were randomized (Arm A: 3 and Arm B: 5). Two pts were not randomized due to worsening PS. During part 2, the most common Grade ≥ 3 AEs were haematological, including reversible lymphopenia, thrombocytopenia and neutropenia, and were more common in Arm B. One pt with SD after 12 weeks received a 2nd injection of 90Y-OTSA101, but experienced fatal hemoptysis. No objective response was observed. Best response was SD in 5/8 pts lasting up to 21 weeks for 1 pt. Conclusions: This FIH shows that radioimmunotherapy targeting FZD10 is feasible and safe in SyS pts. Tumor uptake was heterogeneous but sufficient to select 50% of pts for 90Y-OTSA101 treatment. Due to limited sample size, further clinical investigations are needed to assess the therapeutic activity of 90Y-OTSA101 with a recommended dose of 1110MBq of 90Y. Clinical trial information: NCT01469975.

TPS5607Background: Olaparib (Lynparza) is an oral PARP inhibitor indicated in the EU for the maintenance treatment of patients (pts) with platinum-sensitive relapsed BRCA-mutated high grade serous ...

TPS11620Background: Vemurafenib (V) is registered in monotherapy for the treatment of adult patients (pts) with BRAF V600 mutation (mut) unresectable or metastatic melanoma but responses were obser...

TPS2083Background: Therapeutic options are limited for refractory/relapsed adult medulloblastoma with activation of sonic hedgehog pathway (SHH-MB). Inhibition of this pathway may offer an attracti...

10506 Background: GIST is the most common mesenchymal neoplasm of the gastrointestinal tract. Imatinib followed by sunitinib then regorafenib is the usual sequence in advanced setting. P is effecti...

TPS6106 Background: Patients with locally advanced/metastatic progressive RAIR-DTC usually have a poor prognosis and may receive tyrosine kinase inhibitors (TKI) as first line therapy. Pazopanib (P...

3033 Background: Lymphopenia is an independent predictive and prognostic factor for chemotherapy (CT)-induced death, febrile neutropenia, overall survival and progression in several cancers, includ...

501 Background: Combination of P+BEV significantly improves progression-free survival (PFS) in MBC pts, but is associated with adverse events (AEs), mainly neuropathy and fatigue worsening over tim...

510 Background: Hormone resistance is linked in part to cross-talk between ER signalling and PI3K/Akt/mTOR pathway. Following results of the BOLERO-2 trial, everolimus (E), a potent mTOR inhibitor, has recently been approved in combination with exemestane in women with HR+ MBC refractory to aromatase inhibitor (AI). However, E is frequently associated with specific toxicities, and predictive markers of efficacy are needed. We report here the final results of translational studies within the TAMRAD randomized Phase II trial, comparing tamoxifen (TAM) to TAM+E in AI pre-treated MBC. Methods: Tumor samples from 51 patients among the 111 treated in the TAMRAD trial were retrieved. Hot spot mutations of PI3K (exon 9-20), and KRAS (exon 2) were described. TMA analysis evaluated IHC expression of PTEN, pAkt, PI3K, LKB1, S6K, pS6K, 4EBP1, p4EBP1, and eIF4E. Exploratory analysis of E efficacy in each biomarker subgroup (high vs low expression defined by median percentage of marked cells) was done. Results: Patients characteristics and treatment efficacy among this sub-population were similar to the results from the whole population: Time to progression was 10 months for the TAM+E treated patients vs. 5.5 months for the TAM treated patients, HR: 0.59 (95% CI 0.33-1.07). PI3K-Akt pathway: All patients derived benefit from E regardless of PI3K mutational status, PTEN or pAkt expression. Surprisingly, E efficacy was greater in patients with low PI3K expression (n=12, HR=0.11, 95%CI 0.01-0.96) than in patients with high PI3K expression (n= 28, HR=0.9; 95%CI 0.49-2.41) PI3K independent pathway: Patients with low expression of the anti-oncogene LKB1 derived greater benefit from E (n=22, HR=0.33; 95%CI 0.13-0.89) than patients with high LKB1 expression (n=25, HR=0.75; 95%CI 0.32-1.74) mTOR downstream effectors: Patients with high p4EBP1 (n=27, HR=0.37; 95%CI 0.15-0.90) or low 4EBP1 (n=21, HR=0.39; 95%CI 0.14-1.08) were the subgroups most likely to benefit from E. Conclusions: Those results are in favor of a better efficacy of E for patients with PI3K independent activation of mTOR. If confirmed, they could have important implications for future patient selection. Clinical trial information: NCT01298713.

509 Background: With an incidence of 30%-40%, BM are common complications of HER2+ MBC. Their therapeutic management remains a challenge. As responses on central nervous system (CNS) localization have been reported with L+C combination after WBR, we sought to evaluate the clinical interest of this combination as 1st line treatment for BM in HER2+ MBC patients (pts) with the aim to avoid or to delay WBR. Methods: Eligible pts had HER2+ MBC with BM not previously treated with WBR, C or L. Pts received L1250 mg/day and C2000 mg/m2/day, days 1-14, every 21 days. The primary endpoint was a centrally assessed CNS objective response (CNS-OR) defined as a ≥50% volumetric reduction of CNS lesions in the absence of increasing steroid use, progressive neurologic symptoms, or progressive extra-CNS disease. Using a Simon’s optimal two-stage design with a minimum interesting CNS-OR rate of 20%, 41 evaluable patients were needed. Secondary endpoints included: time to progression (TTP) for both CNS and extra CNS disease;...

10097 Background: Currently, targeted therapies are not registered in advanced STS relapsing after standard chemotherapy. Several phase II trials reports promising results for some particular coupl...