Citations

6080 Background: Alterations in RET are targetable oncogenic drivers in TC. Pralsetinib is a highly potent, selective RET inhibitor, with demonstrated efficacy in pts with RET-altered TC. In a previous analysis of the Phase I/II ARROW trial (NCT03037385; data cutoff: 22 May 2020), overall response rates [ORR; measurable-disease population] with pralsetinib at 400 mg once daily (QD) were 60% (33/55) and 71% (15/21) in pts with RET-mutant medullary TC ( RET-mutant MTC) who had received prior multikinase inhibitors cabozantinib and/or vandetanib (C/V), and those who were treatment naïve, respectively, and 89% (8/9) in pts with previously treated RET fusion-positive TC ( RET-fp TC). Here we report an updated analysis of these cohorts in the intention-to-treat (ITT) population. Methods: Adult pts with RET-altered locally advanced/metastatic TC who had enrolled in ARROW and initiated pralsetinib at 400 mg QD, were included. Phase II primary endpoints: ORR (by blinded independent central review, per RECIST v1.1) and safety. Efficacy endpoints for this analysis were assessed in the ITT population. Safety was assessed in all pts with RET-altered TC who initiated pralsetinib at 400 mg QD. Enrolment cutoff: 23 August 2020 for the ITT population; data cutoff: 12 April 2021. Results: The ITT population comprised 145 pts with RET-mutant MTC (with or without prior systemic therapy, including C/V) and 22 pts with RET-fp TC, 21 of whom had received prior systemic therapy (including multikinase inhibitor[s] and/or radioactive iodine). In pts with RET-mutant MTC who had received prior C/V (n = 67), ORR was 51% (34/67; 95% CI 38–63; 2 complete responses [CR]; 32 partial responses [PR]), median duration of response (DoR) was 25.8 months (95% CI 18.0–not reached [NR]) and median progression-free survival (PFS) was 24.9 months (95% CI 19.7–31.2). In treatment-naïve pts with RET-mutant MTC, ORR was 72% (48/67; 95% CI 59–82; 4 CR; 44 PR), and median DoR and median PFS were not reached. In pts with previously treated RET-fp TC, ORR was 86% (18/21; 95% CI 64–97; 3 CR; 15 PR), median DoR was 17.5 months (95% CI 16.0–NR) and median PFS was 19.4 months (95% CI 13.0–NR). Median overall survival (OS) was not reached in any of the cohorts. The safety population comprised 172 pts with RET-altered TC treated at 400 mg QD. The most common treatment-related adverse events (TRAEs) were increased aspartate aminotransferase (n = 67; 39%), anemia (n = 60; 35%), hypertension (n = 57; 33%) and decreased white blood cell count (n = 52; 30%). Serious TRAEs were reported in 27 pts (16%); the most frequent was pneumonitis (n = 5; 3%). Nine pts (5%) discontinued pralsetinib due to a TRAE and one patient ( < 1%) died due to a TRAE ( pneumocystis jirovecii pneumonia) following 44 days ( < 3 cycles) on pralsetinib. Conclusions: In this updated analysis including more pts, pralsetinib continues to be efficacious with a manageable safety profile in pts with RET-altered TC. Clinical trial information: NCT03037385.

Abstract The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.

9089 Background: RET fusions are targetable oncogenic drivers in 1–2% of non-small cell lung cancer (NSCLC). ARROW (NCT03037385) supported the US FDA approval of pralsetinib, a highly potent oral selective RET inhibitor for RET-altered NSCLC and thyroid cancer. Here, we present updated results for a larger population of patients with RET fusion–positive NSCLC enrolled in ARROW. Methods: ARROW is a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 expansion cohorts included patients with RET fusion–positive NSCLC. Initially, all treatment-naïve patients were not candidates for platinum-based therapy, a requirement removed by protocol amendment in July 2019. Primary objectives are overall response rate (ORR; blinded independent central review [BICR] per RECIST v1.1), assessed for patients with baseline measurable disease, and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off), for patients who initiated pralsetinib 400 mg QD by May 22, 2020 (enrollment cut-off). Efficacy results, including analyses for treatment-naïve patients enrolled after eligibility criteria were revised to allow candidates for platinum-based therapy, are shown in the Table. Conclusions: Pralsetinib showed rapid, potent, and durable clinical activity in patients with RET fusion-positive NSCLC (regardless of prior therapies), including poor prognosis patients not eligible for platinum-based therapy. Overall, pralsetinib was well-tolerated. These data highlight the need for RET testing early in the course of disease to identify candidates who may benefit from treatment with pralsetinib. Clinical trial information: NCT03037385. [Table: see text]

TPS2657 Background: T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor expressed on subsets of T cells and NK cells. SEA-TGT is an effector-function enhanced human mAb that targets TIGIT with pico-molar affinity and blocks TIGIT’s interaction with CD155 and CD112. SEA-TGT was developed to have amplified binding to and engagement of Fcγ receptors. Enhanced effector function increases TIGIT+ T-regulatory cell depletion, enhances innate immune cell activation, and augments naïve and memory CD8+ T-cell responses. Preclinically, SEA-TGT elicits superior anti-tumor immune responses compared to other TIGIT mAbs without effector-enhanced backbones, with curative anti-tumor activity as monotherapy and in combination with other immune-modulators. Methods: This phase 1, open-label, multicenter, dose-escalation/expansion study (NCT04254107) is assessing the safety, tolerability and preliminary activity of SEA-TGT monotherapy in up to 205 adults (≥18 years) with histologically or cytologically confirmed relapsed, refractory, or progressive metastatic solid tumors (non-small cell lung, gastric/GE junction carcinomas, cutaneous melanoma, head and neck squamous cell carcinoma, bladder cancer, ovarian cancer or triple-negative breast cancer) or lymphomas (classical Hodgkin lymphoma, diffuse large B-cell lymphoma, or peripheral T-cell lymphoma, not otherwise specified). SEA-TGT will be infused on Day 1 of 21-day cycles. In Part A, the safety and tolerability of SEA-TGT will be assessed in ̃25 subjects to identify the maximum tolerated dose and recommended phase II dose (RP2D). In Part B, the safety and antitumor activity of the RP2D will be assessed in ̃180 subjects in disease-specific expansion cohorts. Primary endpoints are adverse events, laboratory abnormalities, dose-limiting toxicities, and dose-level safety and activity. Secondary endpoints are objective response (OR) rates, duration of OR, complete response, progression-free survival, overall survival, PK, and antidrug antibodies. Exploratory biomarkers of SEA-TGT-mediated pharmacodynamic (PD) effects, PK-PD correlations, and correlative analyses of predictive and PD measurements with response, toxicity, and resistance will be explored. The study was opened April 2020 and is enrolling across sites in North America and Europe. Clinical trial information: NCT04254107.

3079 Background: RET fusions are targetable oncogenic drivers in multiple solid tumor types. ARROW study (NCT03037385) data supported the US FDA approval of pralsetinib, a once-daily (QD) oral highly potent and selective RET inhibitor, for RET-altered metastatic non-small cell lung cancer (NSCLC) and advanced/metastatic thyroid cancer. Here we provide an update on the clinical activity of pralsetinib in patients (pts) with advanced RET fusion-positive solid tumors other than NSCLC and thyroid cancer (“other” RET fusion–positive solid tumors). Methods: The global ongoing ARROW study (84 sites in 13 countries) includes phase 1 dose-escalation (30–600 mg [QD or twice daily]) and phase 2 expansion cohorts (400 mg QD) defined by tumor type and RET alteration status. Primary objectives are overall response rate (ORR; blinded independent central review per RECIST v1.1) and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off) for 21 pts with other RET fusion–positive solid tumors enrolled by May 22, 2020 (enrollment cut-off) (lung other than NSCLC, n = 4; pancreatic, n = 3; colon, n = 3; cholangiocarcinoma, n = 3; unknown primary [UP], n = 2; other, n = 6). Overall, 11 (52%) pts received ≥2 prior lines of therapy for metastatic disease. The most common RET fusion partners were CCDC6 and KIF5B (24% each), NCOA4 (19%), other (10%), and unknown (24%). Two pts with colon cancer were excluded from efficacy analyses due to other driver mutations ( KRAS, PIK3CB). In 19 evaluable pts, ORR was 53% (95% CI, 29–76) with 2 (11%) complete responses (CR) and 8 (42%) partial responses (PR). Responses occurred across multiple tumor types including 3/3 pts with pancreatic cancer (including a CR ongoing at 20.8 months on treatment), 2/2 pts with UP, 2/3 pts with cholangiocarcinoma, and in pts with mesenchymal, salivary duct, and lung carcinoid tumors. Median duration of response was 19.0 months (95% CI, 5.5–not estimable). Clinical benefit rate (proportion with CR, PR, or stable disease persisting ≥16 weeks) was 68% (95% CI, 43–87). Tumor shrinkage was observed in 89% of 18 evaluable pts with post-baseline tumor assessment. In all pts enrolled in ARROW who received pralsetinib 400 mg QD irrespective of tumor type (n = 471) the most common (≥25%) treatment-related adverse events (TRAEs) were increased aspartate aminotransferase (39%), anemia (35%), increased alanine aminotransferase (28%), constipation (26%), and hypertension (25%). Overall, 6% of pts discontinued treatment due to TRAEs. Conclusions: Pralsetinib showed robust, durable antitumor activity in patients with multiple RET fusion‒positive, heavily pre-treated, advanced solid tumors, and was well tolerated. These data highlight the need for broad RET testing to identify candidates who could benefit from treatment with pralsetinib. Enrollment of patients with other RET fusion–positive solid tumors in ARROW is ongoing. Clinical trial information: NCT03037385.

3036 Background: The presence of HER2 expressing (HER2+) circulating tumor cells (CTCs) occurs often in metastatic breast cancer (MBC) patients (pts). We have previously showed that the ratio among CTCs expressing high level of HER2 and the total number of HER2+ CTCs (circulating HER2 ratio, cHer2 ratio) has a prognostic role in MBC patients. Here we further investigate the role of the cHER2 ratio in the process of metastatic spread. Methods: Under IRB-approved study we prospectively analyzed blood samples of patients with MBC enrolled before starting a new line of therapy. Samples were collected from pts treated at Northwestern University (Chicago, IL) between 2016 and 2020. CTCs were enumerated through CellSearch (Menarini Silicon Biosystems, Bologna, Italy) and characterized for HER2 expression using the CellSearch CXC Kit. HER2+ CTCs were divided in 3 different categories (1+,2+,3+) leaning on fluorescence intensity. Pts with <5 CTCs (stage IV indolent) were excluded from the analysis. The cHER2 ratio, defined as the sum of 2+ CTCs and 3+ CTCs divided by the total number of HER2+ CTCs, was used to split the remaining pts in 2 different cohorts: cHER2 ratio high (> 0.75) (cHER2high) and cHER2 ratio low (≤0.75) (cHER2low). The frequency of each metastatic site (i.e. liver, lung, central nervous system, bone, lymph nodes, skin/soft tissue, serosa) and the total number of different sites involved (1-7, ≤2 and >2 sites) were compared among the two sub-populations and analyzed through Fisher exact test. Results: Out of 98 pts enrolled, 77 were classified as cHER2low and 21 as cHER2high. We observed a higher frequency of oligometastatic pts (≤2 sites involved) in the cHER2high cohort (16, 76%), compared to only 29 (37%) in the cHER2low (p<0.005). Moreover, the cHER2 ratio was associated with a tropism toward specific sites of disease spread with higher incidence of liver, lung and lymph nodes metastases in the cHER2low cohort (p<0.05). No other statistical associations were observed in respect of specific organ tropism. The frequency of involvement for each metastatic site among the two cohorts are reported in the table. Conclusions: Measuring CTCs enumeration and HER2 expression we identified two cohorts, cHER2high and cHER2low, associated with distinct patterns of metastatic spread. The cHER2low pts were correlated to multiple sites of metastatic involvement, with particular tropism toward liver, lung and lymph nodes. These results confirm the prognostic role of the cHER2 ratio, suggesting a peculiar biological meaning of the HER2+ 1+ CTCs.[Table: see text]

467 Background: Recent tumor-agnostic drug approvals have resulted in a paradigm shift in cancer treatment away from organ/histology specific indications to biomarker-guided tumor-agnostic approaches. Pralsetinib is a potent and selective RET inhibitor, which has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with metastatic RET fusion–positive non-small cell lung cancer (NSCLC) and is under New Drug Application review for RET mutant thyroid cancers by the FDA. RET fusions occur in up to approximately 7‒8% of patients with gastrointestinal malignancies, including pancreatic, liver, and colorectal cancers. There are currently no approved selective RET inhibitors for patients with RET fusion–positive solid tumors other than NSCLC and thyroid cancer. Here, we present data on the clinical activity of pralsetinib in patients with RET fusion–positive solid tumor types other than NSCLC enrolled in the Phase I/II ARROW study (NCT03037385). Methods: ARROW consists of a phase I dose escalation (30–600 mg once [QD] or twice daily) followed by a phase II expansion (400 mg QD) in patients with advanced RET-altered solid tumors. Primary objectives are overall response rate (ORR), per RECICT v1.1 and safety. Results: A total of 13 patients with RET fusion–positive thyroid cancer (12 papillary, 1 poorly differentiated; enrollment cutoff July 11, 2019) and 14 patients with RET fusion–positive solid tumors other than NSCLC and thyroid (3 pancreatic, 3 colon, 2 cholangiocarcinoma, 6 other; enrollment cutoff November 19, 2019) were enrolled in ARROW and received pralsetinib. At the February 13, 2020, data cutoff, the ORR (blinded central review) in response-evaluable patients with RET fusion–positive thyroid cancer was 91% (10/11; 95% CI: 59‒100) and disease control rate was 100% (95% CI: 72‒100). Treatment was ongoing in 7 of 11 patients. In RET fusion–positive solid tumors other than NSCLC and thyroid, ORR (investigator’s assessment) was 50% (6/12; 95% CI: 21‒79) and responses were observed in all patients with pancreatic cancer (3/3) and cholangiocarcinoma (2/2). Treatment was ongoing in 6 of 12 patients, including 2 of 3 patients with pancreatic cancer and 1 of 2 patients with cholangiocarcinoma. Responses were observed across multiple fusion genotypes. In the 27 patients with RET fusion–positive tumors other than NSCLC, most frequent treatment-related adverse events (TRAEs) were grade 1–2, and included anemia (33%), increased aspartate aminotransferase (33%), decreased white blood cell count (33%), hypertension (30%), increased alanine aminotransferase (26%), hyperphosphatemia (19%), and neutropenia (19%). No patients discontinued due to TRAEs. Conclusions: Pralsetinib demonstrated broad and durable antitumor activity across multiple advanced solid tumor types, regardless of RET fusion genotype, and was well tolerated. The study is ongoing. Clinical trial information: NCT03037385.

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS–CoV‐2) has given rise to a pandemic of unprecedented proportions in the modern era because of its highly contagious nature and impact on human health and society: coronavirus disease 2019 (COVID‐19). Patients with cardiovascular (CV) risk factors and established CV disease (CVD) are among those initially identified at the highest risk for serious complications, including death. Subsequent studies have pointed out that patients with cancer are also at high risk for a critical disease course. Therefore, the most vulnerable patients are seemingly those with both cancer and CVD, and a careful, unified approach in the evaluation and management of this patient population is especially needed in times of the COVID‐19 pandemic. This review provides an overview of the unique implications of the viral outbreak for the field of cardio‐oncology and outlines key modifications in the approach to this ever‐increasing patient population. These modifications include a shift toward greater utilization of cardiac biomarkers and a more focused CV imaging approach in the broader context of modifications to typical practice pathways. The goal of this strategic adjustment is to minimize the risk of SARS–CoV‐2 infection (or other future viral outbreaks) while not becoming negligent of CVD and its important impact on the overall outcomes of patients who are being treated for cancer.

109 Background: RET gene fusions are targetable oncogenic drivers in multiple tumor types, including up to 20% of papillary thyroid cancers (PTC). Pralsetinib is an investigational, highly potent, selective inhibitor of oncogenic RET alterations. In the registration-enabling Phase 1/2 ARROW study (NCT03037385), pralsetinib demonstrated an overall response rate (ORR; response-evaluable patients [REP], central review) of 73% (19/26) in treatment-naïve patients and 61% (49/80; 2 pending confirmation) in platinum-exposed patients with RET fusion+ non-small cell lung cancer (NSCLC) and was well tolerated (data cut-off November 18, 2019). We provide an update on the clinical activity of pralsetinib in other RET fusion+ solid tumor types. Methods: ARROW consists of a phase 1 dose escalation (30–600 mg once [QD] or twice daily) followed by a phase 2 expansion (400 mg QD) in patients with advanced RET-altered solid tumors. Primary objectives were ORR and safety. Results: As of November 18, 2019, 29 patients with metastatic solid tumor types other than NSCLC (16 PTC, 1 undifferentiated thyroid, 3 pancreatic, 3 colon, 6 other) bearing a RET fusion have received pralsetinib. Efficacy data are presented for REP enrolled by July 11, 2019. In patients with thyroid cancer that is RET fusion+, ORR (investigator assessment) was 75% (9/12; all confirmed). Median (range) duration of response (DOR) was 14.5 (3.7+, 16.8) months (mo), with 67% of responding patients continuing treatment. Two patients with stable disease were continuing treatment at 11.5+ and 19.3+ mo. In other RET fusion+ cancers, ORR was 60% (3/5; all confirmed) with partial responses in 2/2 patients with pancreatic cancer (DOR 5.5, 7.4+ mo) and 1 patient with intrahepatic bile duct carcinoma (DOR 7.5 mo). Two patients with colon cancer had stable disease for 7.3 and 9.3 mo. Responses were observed across multiple fusion genotypes. In the entire safety population (all patients treated with 400 mg QD pralsetinib, regardless of diagnosis; n = 354), most treatment-related adverse events (TRAEs) were grade 1-2, and included increased aspartate aminotransferase (31%), anemia (22%), increased alanine aminotransferase (21%), constipation (21%) and hypertension (20%). Only 4% of patients in the safety population discontinued due to TRAEs. Conclusions: Pralsetinib demonstrated broad and durable antitumor activity across multiple advanced solid tumor types, regardless of RET fusion genotype, and was well tolerated. The study is ongoing and still enrolling patients in this cohort. Clinical trial information: NCT03037385.