Sarkome/Seltene Tumore

V711 Klinischer Nutzen mit Ripretinib als 4. Linientherapie in Patienten mit fortgeschrittenem gastrointestinalem Stromatumor: Aktualisierung aus der Phase 3 INVICTUS Studie
Sebastian Bauer, Essen, D

Introduction: Ripretinib is an FDA-approved broad-spectrum KIT and PDGFRA switch-control tyrosine kinase inhibitor (TKI). In INVICTUS, a randomized, double-blind, placebo-controlled trial in ≥4th-line advanced GIST, ripretinib compared with placebo (PBO) significantly improved progression-free survival (PFS, 6.3 vs. 1.0 months) reducing the risk of disease progression or death by 85% and showed a clinically meaningful improvement in overall survival (OS, 15.1 vs 6.6 months); data as of May 31, 2019. Ripretinib was associated with a well-tolerated safety profile. Here, we report the updated results with an additional 9 months of follow-up as of March 9, 2020.

Methods: Patients with advanced GIST previously treated with at least imatinib, sunitinib, and regorafenib were randomized (2:1) to ripretinib 150 mg QD or PBO. Upon disease progression determined by blinded independent central review (BICR), patients on PBO could cross over to ripretinib 150 mg QD. All patients who received 150 mg QD and progressed radiographically could receive 150 mg BID. Updated PFS by BICR, OS, and safety are reported here with data as of March 9, 2020.

Results: Overall, 129 patients were randomized and 128 received treatment (ripretinib 150 mg QD, n=85; PBO, n=43). Patients randomized to ripretinib had a median PFS (mPFS) of 6.3 (95% CI 4.6─8.1) vs. 1.0 (95% CI 0.9─1.7) months for patients on PBO with a hazard ratio (HR) of 0.16. The median OS (mOS) in the ripretinib arm was not reached (95% CI 13.1─NE) vs. 6.3 (95% CI 4.1─10.0) months in the PBO arm with a HR of 0.43. No new safety concerns emerged with longer exposure to ripretinib.

Conclusions: Evaluation of mPFS and OS in the phase III INVICTUS randomized trial, with a cut-off date for analysis approximately 9 months after the primary results, has shown an improvement in the mOS in the ripretinib arm from 15.1 months to not reached (95% CI 13.1─NE) and a similar mPFS of 6.3 months in the ripretinib arm. These updated results confirm the clinically meaningful benefit in PFS and OS for ripretinib with a well-tolerated safety profile in patients with advanced GIST treated with at least 3 prior TKIs, including imatinib.

Clinical trial identification: NCT03353753. Funding: Deciphera Pharmaceuticals, LLC.

(Encore abstract: original presentation at ESMO 2020.)

V338 Ein neuartiger theranostischer Ansatz für Sarkome: Einblicke in die diagnostische und therapeutische Verwendung von FAP-Radioliganden
Rainer Hamacher, Essen, D

Introduction: Bone and soft tissue sarcomas express fibroblast activation protein (FAP) on tumor cells and associated fibroblast. Therefore, FAP is a promising therapeutic and diagnostic target. Novel radio- labelled FAP-Inhibitors (FAPI) have shown high tumor uptake in positron emission tomography (PET) in sarcoma patients.

Methods: We report on 47 patients with bone or soft tissue sarcomas undergoing diagnostic PET imaging with [68Ga]Ga-FAPI-46 (68Ga-FAPI-PET). Of these patients, 43 patients also underwent 18F-Fluordesoxyglucose PET (FDG). 68Ga-FAPI-PET uptake intensity and histopathological FAP-expression was analyzed with Spearman's r correlation. Moreover, detection rate and positive predictive value (PPV) were evaluated. For 6 patients we report initial findings for radioligand therapy (RLT) with [90Y]Y-labelled FAPI-46 ([90Y]Y FAPI-46).

Results: We show a significant association between 68Ga-FAPI-PET uptake intensity and histopathological FAP-expression (Spearman's r = 0.43; p = 0.03). By histopathological validation PPV was 1.00 (95% CI, 0.87-1.00) on a per-patient and 0.97 (95% CI, 0.84-1.00) on a per-region basis for any tumor. The detection rate on a per-patient basis in FAPI- and FDG-PET was 76.6% and 81.4%, respectively. Compared to FDG-PET, 68Ga-FAPI-PET resulted in an upstaging in 8 patients and downstaging in 3 patients.

Six patients received [90Y]Y-FAPI-46 RLT. Post-treatment scintigraphy demonstrated sufficient [90Y]Y- FAPI-46 uptake in tumor lesions in 5 patients. G3 thrombocytopenia was noted in one patient. No acute toxicities attributed to [90Y]Y-FAPI-46 were noted. Radiographic disease control was noted in three patients.

Conclusions: FAPI-PET is a valuable diagnostic tool in patients with sarcoma. We confirm an association of tumoral FAPI-PET uptake intensity and histopathological FAP expression in sarcoma patients. We further demonstrate high accuracy of FAPI-PET and, when compared to FDG-PET, similarly high detection rate and reproducibility. Moreover, FAP-targeted RLT with [90Y]Y-FAPI-46 was tolerated well with a low rate of attributable adverse events and we observe signs of clinical activity.


V184 Wirksamkeit und Sicherheit von Selpercatinib bei RET-Fusions-positiven Krebsarten außer Lungen- oder Schilddrüsenkrebs

Oliver Gautschi, Luzern 16, CH

Introduction: Selpercatinib is approved in multiple countries for treating RET fusion-positive lung or thyroid cancers. RET fusions are implicated in the pathogenesis of other cancers. Selpercatinib's efficacy and safety were explored in patients (pts) with RET fusion-positive non-lung/non-thyroid cancers in a global, multicenter, registrational trial.

Methods: Adults with locally advanced/metastatic RET fusion-positive non-lung/non-thyroid solid tumors enrolled in the phase 1/2 LIBRETTO-001 trial were included in this analysis (data cut-off 19Mar2021). Following dose escalation, pts received 160mg orally, twice daily (recommended dose). Pts enrolled long enough to allow 6-month follow-up from their first dose comprised the efficacy-evaluable population. Response was assessed by investigators. Primary endpoint: objective response rate (ORR). Secondary endpoints included duration of response (DoR)/time to response/safety.

Results: 32 pts with RET fusion-positive non-lung/non-thyroid cancers included 12 unique tumor types: 9 pancreatic/9 colon/2 each of breast, salivary, sarcoma, and unknown primary/1 each of carcinoid, rectal neuroendocrine, small intestine, xanthogranuloma, ovarian and pulmonary carcinosarcoma. Median age=48 years (range 22-85). 29 pts received prior systemic therapy (median prior lines=2, range 0-9). ORR=47% (N=15/32, 95%CI=29-65). Objective responses were observed in 9 unique cancer types including colon, pancreatic, carcinoid, small intestine, salivary, xanthogranuloma, breast, ovarian and sarcoma, and 5 additional patients had stable disease lasting ≥16 weeks. Median time to response=1.9 months (range 0.7-7.3). Median DoR was not reached (median follow-up time=13 months). Responses were ongoing in 73% (11/15) of pts. Safety among this population was consistent with the overall selpercatinib safety database. No patients in this cohort discontinued due to treatment- related AEs.

Conclusions: Selpercatinib demonstrated promising antitumor activity in RET fusion-positive non- lung/non-thyroid cancers, including multiple treatment-refractory GI malignancies. Broad-based genomic profiling is essential to identify actionable oncogenic drivers, including RET fusions. Selpercatinib's safety and efficacy will continue to be explored in pts with these cancers in the ongoing LIBRETTO-001 study.


V213 Einfluss des interdisziplinären Sarkomboards und dessen Entscheidungen auf das Outcome von Patienten mit primärem Weichteilsarkomen

Annika Strönisch, Berlin, D

Introduction: Due to their rarity and heterogeneity, the management of soft tissue sarcoma (STS) still poses significant challenges. Treatment at specialized sarcoma centers with recurrent discussion in an interdisciplinary sarcoma board (ISB) is crucial for therapeutic quality. However, there exists only limited data about the clinical significance of ISB implementation.

Methods: We performed a retrospective data analysis of STS patients (pts) presented to the ISB at the Charité - Universitätsmedizin Berlin from 2015-2020. Included were pts in firstline therapy who received at least one ISB recommendation (ISB-R). Data was retrieved via the hospital archives and the outpatient network.

Results: A cohort of 230 pts (47% female, 53% male) with a median age of 58 years (19-96 years) was identified. Histological grading was predominantly high in n=153 (67%) cases.

Overall 196 pts (86%) had a localized disease. In n=73 (37%) of those cases, surgery was performed before ISB presentation. In total, for 138 pts (70%) surgery was recommended, in n=102 (52%) combined with an additional modality within a neo- and/or adjuvant concept. OS and PFS was significantly improved by complete implementation of the ISB-R (p< 0.001). The omission of one recommended modality due to patient refusal or physician ́s decision was associated with an increased risk of death (HR for death 5.4; 95%CI 1.9-15.4). Pts for whom it was impossible to follow the ISB-R due to rapid progression or complications had the worst prognosis (n=26, 13%; HR for death 10.4; 95%CI 4.5-24.3). A Charlson comorbidity score >2 also resulted in a higher risk of death (HR for death 1.4; 95%CI 1.2-1.7). Neither histological grading nor age had a significant influence.

In metastasised disease (n=33, 14%), chemotherapy was most frequently recommended (n=30, 91%). In 15 pts (45%), additional local treatment was advised. Rapid progression or complications leading to the inability to implement the ISB-R (n=16, 49%) was associated with shorter OS (p< 0.01). Likewise, an ECOG > 0 led to shorter OS (p=0.04). In contrast, age or sex showed no effect.

Conclusion: In our STS cohort, treatment adherent to the ISB-R had a significant impact on PFS and OS in STS pts. In analogy to international reports, we hereby emphasize the value of early and consistent interdisciplinary decision-making in STS. Further implementation of defined quality parameters of the German Cancer Society will help to improve outcome in STS.


V101 Langzeit-Wirksamkeit und -Verträglichkeit von Larotrectinib bei Patienten mit TRK-Fusionstumoren - eine integrierte Auswertung
Serge Leyvraz, Berlin, D

Background: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions encode tropomyosin receptor kinase (TRK) fusion proteins, which are oncogenic drivers in various tumor types. Larotrectinib is a first- in-class, highly selective, CNS-active TRK inhibitor approved to treat adult and pediatric patients with TRK fusion cancer. Larotrectinib demonstrated an objective response rate (ORR) of 78% and a median progression-free survival (PFS) of 36.8 months in an integrated analysis of 175 patients (pts) with non- primary CNS TRK fusion cancer (McDermott et al, ESMO 2020). We report updated efficacy and safety data with longer follow-up in an expanded dataset.

Methods: Data were pooled from 3 clinical trials of pts with non-primary CNS TRK fusion cancer treated with larotrectinib. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was assessed by investigators using RECIST v1.1. Data cutoff: July 2020.
Results: 218 pts were treated with larotrectinib, of which 206 were evaluable for efficacy. There were 21 different tumor types, the most common being soft tissue sarcoma (STS [46%], including infantile fibrosarcoma [20%] and other STS [26%]), thyroid (13%), salivary gland (11%), lung (9%), and colorectal (5%). The median age was 38.0 years. Pts were heavily pretreated with 45% having received 2 or more prior lines of systemic therapy; 27% had 0 prior lines of systemic therapy. The ORR was 75% (95% CI 68-81): 45 (22%) complete response, 109 (53%) partial response (PR), 33 (16%) stable disease (SD), and 13 (6%) progressive disease (PD). Nineteen pts had brain metastases at baseline, with 15 evaluable for efficacy. The ORR for pts with brain metastases was 73% (95% CI 45-92): 11 PR, 2 SD, and 2 PD. Among all evaluable pts, the median time to response was 1.8 months (range 0.9-9.1). Median duration of response was 49.3 months (95% CI 27.3-not estimable). Median PFS was 35.4 months (95% CI 23.4-55.7). Median overall survival (OS) was not reached and 36-month OS was 77% (95% CI 69-84). Treatment-related adverse events (TRAEs) were mainly Grade 1-2, with 18% having Grade 3-4 TRAEs. Only 2% of pts discontinued due to TRAEs.

Conclusions: These results highlight the importance of testing for NTRK gene fusions in pts with cancer because the majority of pts with TRK fusion cancer treated with larotrectinib had long-term clinical benefit. The safety profile continued to be favorable and no new safety signals were identified.