Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-mutant MTC and RET fusion-positive thyroid and lung cancers. In the previous report, duration of response (DoR) and progression free survival (PFS) follow-up (f/u) was limited. Updated analysis of selpercatinib in pts with RET-mutant MTC in LIBRETTO-001 (NCT03157128) was conducted after an additional f/u of 15 months. Primary endpoint was objective response rate (ORR, RECIST 1.1) by independent review committee (IRC). Secondary endpoints included DoR, PFS, and safety. Efficacy of selpercatinib was evaluated in cabozantinib/vandetanib (cab/van) naïve pts (N=142) and cab and/or van pre-treated pts (N=151) (Table). Naïve and pre-treated pts achieved an ORR of 81.0% and 73.5%, respectively. Despite a median f/u of ∼2 yrs, DoR and PFS data are still immature, with response ongoing in most pts. At 2 yrs, 81.1% of naïve pts and 64.4% of pre-treated pts remained progression free. In the safety population (MTC pts with ≥ 1 dose, N=319), the most common ≥3 grade treatment-emergent adverse events (TEAEs) were: hypertension (21.6%), increased aspartate (7.2%)/alanine (8.2%) aminotransferase, hyponatraemia (7.5%), lymphopenia (6.3%), and diarrhea (6.3%). In total, 23 pts (7.2%) discontinued treatment due to TEAEs, including 13 pts (4.1%) due to treatment related TEAEs.Table: 1656PEfficacy of selpercatinib in RET-mutant MTCCab/van naïve (N=142)Prior cab and/or van (N=151)ORR by IRC, % (95% CI)81.0 (73.6-87.1)73.5 (65.7-80.4)Complete response, n (%)22 (15.5)14 (9.3)Partial response, n (%)93 (65.5)97 (64.2)Stable Disease, n (%)22 (15.5)31 (20.5)Progressive Disease, n (%)2 (1.4)2 (1.3)Not Evaluable (NE), n (%)3 (2.1)7 (4.6)PFS by IRCMedian PFS, months (95% CI)NE (NE-NE)34 (25.7-NE)Censored, %83.162.3PFS rate at 24 months, % (95% CI)81.1 (72.4-87.3)64.4 (55.4-72.0)Median f/u, months24.527.6DoR by IRCMedian DoR, months (95% CI)NE (NE-NE)NE (27.2-NE)Censored, %87.069.4DoR rate at 24 months, % (95% CI)83.7 (73.0-90.4)64.5 (52.9-73.9)Median f/u, mo20.322.9 Open table in a new tab With longer f/u and additional pts, selpercatinib continues to demonstrate very durable responses in MTC patients with or without prior cab/van therapy, suggesting first line use of selpercatinib appears to be highly effective in treatment of MTC. The safety profile is unchanged despite longer duration on treatment. Disclosure: Funded by Eli Lilly and Company.

10009 Background: Activating RET alterations are oncogenic drivers of select pediatric and adult cancers. Selpercatinib is a first-in-class, highly selective and potent, CNS active RET kinase inhibitor. The manageable toxicity profile and durable anti-tumor activity in RET-altered cancers demonstrated in the LIBRETTO-001 phase 1/2 trial led to global approvals of selpercatinib in adults and adolescents with thyroid cancer and adults with NSCLC. Methods: LIBRETTO-121 (JZJJ) is a multicenter phase 1/2 trial in pts 0.5-21 years (yrs) of age with advanced, RET-altered solid or CNS tumors. Enrollment began in June 2019 and is ongoing. Selpercatinib is administered orally as capsule or liquid suspension BID continuously. Dosing started at the adult recommended phase 2 dose (RP2D) equivalent, 92mg/m2 BID, to confirm RP2D in pts ≤2 yrs and > 2 yrs. The phase 1 primary objective is to evaluate safety and dose limiting toxicities (DLTs). The phase 2 primary objective is to determine overall response rate by RECIST 1.1 or RANO by independent review. Results: As of 2-Oct-2020, 11 pts (6 male) aged 2–20 yrs (medullary thyroid cancer, n = 8; papillary thyroid cancer, n = 2; osteosarcoma, n = 1) had been treated (phase 1, n = 4; phase 2, n = 7). At baseline, 7 pts had measurable disease. RET alterations included fusions (n = 2), activating mutations (n = 8) and mutation with unknown clinical significance (n = 1). Prior therapies included surgery (n = 8), chemotherapy (n = 1), vandetanib (n = 1) and radiotherapy (n = 3), while 3 pts were previously untreated. Time on selpercatinib ranged from 0.9-13.4 months and 9 pts remain on treatment. One pt experienced a dose reduction and 2 pts experienced dose interruptions due to treatment-emergent adverse events (TEAEs) (elevated alanine aminotransferase [ALT] and bilirubin). There were no DLTs and no TEAEs that led to discontinuation of selpercatinib. TEAEs in > 15% of pts included elevated alkaline phosphatase (ALP), constipation, headache, elevated aspartate aminotransferase (AST), diarrhea, hyperphosphatemia, hypoalbuminemia, hypothyroidism, nausea, pyrexia, urinary tract infection, vomiting and weight gain. Drug-related TEAEs in > 15% of pts included elevated AST, elevated ALP, hyperphosphatemia and hypothyroidism. One pt reported TEAEs ≥ grade (G) 3 (elevated ALT, G3 and AST, G3) related to selpercatinib. Best response was unconfirmed partial responses in 4 pts, stable disease in 6 pts (two lasting ≥16 weeks) and progressive disease in 1 pt. Conclusions: These findings appear consistent with the adult trial results, showing preliminary evidence of safety and efficacy of selpercatinib in pediatric pts with RET-altered solid tumors. The phase 1 portion in pts ≤2 yrs and phase 2 portion at RP2D of 92mg/m2 BID for pts > 2 yrs are ongoing. Clinical trial information: NCT03899792.

Activating RET gene alterations are common in MTC, yet current RET mutant (mut) MTC Tx options are not ideal for many patients (pts). Despite improvements in progression free survival (PFS) and response rate with multikinase inhibitors (MKI), notable toxicity and tumor resistance may limit their long-term efficacy in RETmut MTC. Selpercatinib (LOXO-292), a selective and potent inhibitor of RET alterations including M918T, MKI resistance-associated V804M, and others, showed evidence of robust antitumor activity [objective response rate (ORR) 73% in phase I/II] and a well-tolerated profile in pts with MKI-naïve, advanced RETmut MTC. This global, open-label, randomized, controlled, phase III trial will compare selpercatinib to physician choice of cabozantinib or vandetanib in pts with MKI-naïve progressive advanced or metastatic RETmut MTC. Pts (n=400) will be randomized 2:1 to Arm A: selpercatinib (160 mg BID) or Arm B: physician choice of cabozantinib (140 mg QD) or vandetanib (300 mg QD). Stratification factors are mutation: M918T vs other and intended Tx if randomized to Arm B: cabozantinib vs vandetanib. For Arm B pts, crossover to selpercatinib is allowed at progression. Tx will continue until progressive disease (PD), unacceptable toxicity, withdrawal of consent or death. Major eligibility criteria are age ≥12 years; unresectable locally advanced or metastatic disease; RETmut identification by PCR or NGS on germline DNA, tumor or blood; sufficient tissue for central analysis of RET mutation; MKI-Tx naive; measurable disease and PD within 14 months by RECIST 1.1; ECOG performance status 0-2; adequate organ function. Exclusion criteria are presence of other oncogenic drivers or symptomatic CNS metastases. Tumor evaluations will be performed every 8 weeks for 24 weeks and then every 12 weeks. Treatment failure free survival, including radiographic PD, unacceptable toxicity (predefined by protocol) or death, is the primary endpoint. The key type I error controlled secondary endpoint is PFS by independent review. Other secondary endpoints are physician assessed PFS, ORR/duration of response, overall survival, PFS2, ORR by RET mutation status, safety profile and pharmacokinetics. NCT04211337. Hannah Davis, PhD, an Eli Lilly and Company employee, provided medical writing support. Eli Lilly and Company. Eli Lilly and Company.

Background The ANNOUNCE trial evaluated the efficacy of the anti-PDGFR alpha antibody olaratumab + dox versus placebo + dox in adults with STS. CT was a secondary safety objective. Methods Treatment included dox 75mg/m2 on Day 1 of a 21-day cycle for up to 8 cycles, with olaratumab/placebo on Days 1, 8 until progression. Use of the cardioprotectant dexrazoxane was allowed with any cycle and recommended with Cycle 5 and beyond. Pts were monitored for left ventricular ejection fraction (LVEF) decreases after 4, 6, 8 cycles and electrocardiogram (ECG) changes in cycles 1 to 9; both were then monitored every 3 months for 1 year, every 6 months for 1 year, then annually. Eligible pts had a LVEF of ≥ 50% at baseline, and were without QTc prolongation, active symptoms of cardiac arrhythmia/dysfunction, and prior anthracycline exposure or mediastinal/pericardial radiation. Results Median age was 57 years. Medical history included cardiac disorders (n = 33; 6.5%) and ECG abnormalities (n = 1; 0.2%). Of the 506 treated pts from both arms, 504 (99.6%) had at least 1 dox dose, of which, 64.0% received at least 1 dose of dexrazoxane, with 61.0% of these pts starting before Cycle 6. Median dox exposure was 6 cycles/450mg/m2; median duration of CT evaluation was 28 weeks. One pt died due to acute cardiac failure after a cumulative dox dose of 441mg/m2. Adverse events (AEs) of cardiac dysfunction/decreased LVEF are summarized (Table). ECG abnormalities considered AEs occurred in 15 (3.0%) pts. Conclusions The ANNOUNCE trial prospectively evaluated CT in a large cohort of dox-treated adults with STS, most of whom received dexrazoxane for cardioprotection. Although LVEF decreases were common with routine monitoring, symptomatic cardiac dysfunction was reported infrequently. Frequency of CT was similar in both arms. Longer safety follow-up may be warranted to determine the true rate of CT with higher cumulative doses of dox. Table . 1671O Cumulative Dox Dose (Pooled) Overall 300 to ≤ 500mg/m2 (n = 114) >500mg/m2 (n = 211) Dox-Olaratumab (n = 257) Dox-Placebo (n = 249) Any ≥G3 Any ≥G3 Any ≥G3 Any ≥G3 Any ≥G3 Cardiac dysfunction a 0 0 18 (15.8) 9 (7.9) 8 (3.8) 2 (0.9) 12 (4.7) 5 (1.9) 14 (5.6) 6 (2.4) Number of Dox Cycles (Pooled) Lowest Post-baseline 4 Cycles (n = 201) 6 Cycles (n = 153) 8 Cycles (n = 158) Dox-Olaratumab (n = 200) Dox-Placebo (n = 201) Decreased LVEF b 44 (21.9) 36 (23.5) 49 (31.0) 96 (48.0) 98 (48.8) Data are presented as n (%). Abbreviations: Dox, doxorubicin; G, grade; LVEF, left ventricular ejection fraction. a Cardiac dysfunction was defined by pre-selected terms from Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query “cardiac failure,” omitting non-specific terms “edema” and “peripheral edema.” b LVEF decrease by 10% from baseline. Clinical trial identification NCT02451943. Editorial acknowledgement Karen Paulsrud, RPh, with Eli Lilly and Company, provided medical writing support. Legal entity responsible for the study Eli Lilly and Company. Funding Eli Lilly and Company. Disclosure R.L. Jones: Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Clinigen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Epizyme; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Deciphera; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: Merck; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Tracon. A.J. Wagner: Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Five Prime; Advisory / Consultancy: Nanocarrier; Honoraria (self): Novartis; Research grant / Funding (institution): Plexxikon; Research grant / Funding (institution): Aadi Bioscience; Research grant / Funding (institution): Karyopharm. A. Kawai: Honoraria (self), Advisory / Consultancy: Eli Lilly and Company. A. Shahir: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. V. Soldatenkova: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. J. Wright: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. W.D. Tap: Shareholder / Stockholder / Stock options: Certis Oncology Solutions; Shareholder / Stockholder / Stock options: Atropos Therapeutics; Honoraria (self), Advisory / Consultancy: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy: EMD Serono; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Immune Design; Honoraria (self), Advisory / Consultancy: Adaptimmune; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Blueprint; Honoraria (self), Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Agios Pharmaceuticals; Honoraria (self), Advisory / Consultancy: NannoCarrier; Advisory / Consultancy: Plexxikon Pharmaceuticals; Licensing / Royalties: Companion Diagnostic for CDK4 inhibitors; Officer / Board of Directors, Editor in Chief: Sarcoma Journal; Officer / Board of Directors, Treasurer: Connective Tissue Oncology Society.

10541 Background: Olaratumab (O), a PDGFRα antagonist, is a targeted human IgG1 monoclonal antibody that specifically binds PDGFRα, blocking PDGF-AA, -BB, and -CC binding and receptor activation, and has improved survival outcomes in adults with advanced sarcoma. Methods: This ongoing Phase 1, multicenter, dose-escalation study (NCT02677116) enrolled patients (pts) aged < 18 years, with a diagnosis of relapsed or refractory solid tumors, to 2 dose levels (Parts A and B) of O combined with fixed doses of standard chemotherapy with doxorubicin (D), vincristine/irinotecan (VI), or high-dose ifosfamide (I). Pts in Part A received 1 cycle (21 days) of O monotherapy at 15mg/kg IV on Days 1 and 8 followed by O + (D, VI, or I) for subsequent 21-day cycles. Each combination arm was complete when 6 pts received 2 full cycles. The primary objective of Part A was to determine the safety and tolerability of O 15mg/kg + (D, VI, or I) based on any dose-limiting toxicity (DLT) and O serum exposure matching between adult and pediatric pts. Results: Pts enrolled by O + chemotherapy regimen (n) were D (11), VI (10), and I (9). One pt (3.3%) experienced a DLT during the DLT period (Cycles 1 and 2), which consisted of grade (G) 4 elevated ALT while on O monotherapy. No ≥G3 infusion- or cardiac-related treatment emergent adverse events (AEs) occurred. Treatment-related AEs (TRAEs) ≥G3 reported in ≥2 pts are presented (Table). Serum concentrations of O in pediatric pts were within expected ranges based on adult exposure. Conclusions: Based on Part A results,O 15mg/kg as monotherapy or in combination with D, VI, or I is tolerable in pediatric pts with relapsed or refractory solid tumors. Part B of this trial is currently enrolling. Clinical trial information: NCT02677116.TRAE, n (%) O + D O + VI O + I G3 G4 G3 G4 G3 G4 ALT increased 0 0 1 (10.0) 0 0 1 (11.1) Anemia 1 (9.1) 0 1 (10.0) 1 (10.0) 3 (33.3) 0 Leukopenia 0 2 (18.2) 0 1 (10.0) 0 3 (33.3) Lymphopenia 0 1 (9.1) 1 (10.0) 0 1 (11.1) 4 (44.4) Neutropenia 0 3 (27.3) 2 (20.0) 1 (10.0) 1 (11.1) 1 (11.1) Thrombocytopenia 0 1 (9.1) 0 1 (10.0) 3 (33.3) 1 (11.1) Vomiting 0 0 1 (10.0) 0 1 (11.1) 0