Mahipal, Amit

248 Background: Esophageal carcinoma is the 6th most common cause of death worldwide. While squamous cell carcinoma (SCC) was the most common among the histologic subtypes in the 20th century, recent reports have demonstrated an increased incidence of adenocarcinoma in both Eastern and Western world. With this changing paradigm of esophageal carcinoma, it is important to estimate the future burden of esophageal carcinoma by histology, age, sex, and race, that could help plan prevention, control, and treatment strategies for this cancer. Methods: We used Surveillance, Epidemiology, and End Results (SEER) 14 registries to obtain incidence data from 2000 to 2016. We applied age-period-cohort models to estimate future esophageal carcinoma incidence rates and the estimated disease burden by multiplying incidence forecasts by corresponding US Census population projections. Results: Our estimate suggests that the incidence (per 100,000 persons) of esophageal adenocarcinoma is increasing in people within the age group of 40-65 years. Our prediction showed that the incidence will increase from 2.12 in 2021 to 2.82 in 2030 (3.2% per year, 95% CI –2.3% to 9.1%, p=0.26). Notably, we noticed a similar marginal increase in incidence among Asians, Black, and Whites in the 40-65 years age group (3.1%, 3.2%, and 4.2%, per year, respectively). White males aged >65 years had the highest incidence of esophageal adenocarcinoma (17.34 in 2021), and incidence decreased 1.3% per year. We noticed a marginally decreased incidence in Black male (-1.1% per year, p=0.71) and Asian male (-3.9% per year, p=0.17) population aged >65 years. Interestingly, we found a decrease in the incidence of SCC in the current age groups 40-65 (-2.7% per year, p=0.31) and >65 years (-4.6% per year, p=0.081). We observed that Asians had the greatest decrease in incidence (-4.3% per year) as compared to that of Blacks (-4.2% per year) and Whites (-2.9% per year), although there was no statistically significant difference in the annual decrease among races. Conclusions: In our study of esophageal cancer, we predict an increased incidence of adenocarcinoma histology subtype in the younger age group (40-65 years) while the SCC subtype will have a decreased trend. Strategies to prevention esophageal adenocarcinoma, including dietary changes, should preferentially target patients <65 years of age.[Table: see text]

192 Background: Rectal cancer treatment paradigm has been evolving over time. Historically, for locally advanced rectal cancer, standard therapy (ST) consisted of neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy. Recently, total neoadjuvant treatment (TNT) approach that delivers both neoadjuvant chemotherapy (CAPOX or FOLFOX) and chemoradiation (or radiation only) prior to surgery is increasingly being utilized. The prognostic and predictive values of mismatch repair deficient (dMMR) in rectal cancer is not well characterized. Most dMMR patients receive the same treatment as MMR proficient (pMMR) patients although there is limited data that dMMR rectal cancer patients may not have the same level of benefits from neoadjuvant treatment. This retrospective study aims to evaluate the clinicopathological/molecular characteristics, disease response, and clinical outcomes in dMMR localized rectal cancer patients. Methods: A retrospective analysis was conducted on consecutive adult patients with a diagnosis of dMMR rectal cancer who were treated at Mayo Clinic between January 2000 to September 2021. Patients who presented with concurrent primary non-colorectal malignancies were excluded. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were collected. Survival was assessed using Kaplan-Meier curves and Cox models were stratified by treatment arms to determine significance of treatment strategies. Results: Forty-one patients were identified with a median age of 45.3 years. Thirty (73.2%) pts were male. The most common MMR were loss of MSH2 and MSH6 (12/42; 29.3%) followed by loss of MLH1 and PMS2 (10/42; 24.4%) and solitary loss of MSH2 (4/42; 9.8%). The treatment, pathological response, and clinical outcomes are listed in table. With a median follow up of 101 months, only 6 patients (14.3%) died and median overall survival was not reached. Conclusions: Our findings showed dMMR localized rectal cancer responded to both ST and TNT with good clinical outcomes.[Table: see text]

8 Background: Standard 1L therapies for mCRC include a fluoropyrimidine with oxaliplatin and/or irinotecan, and a biologic agent. NIVO may enhance antitumor activity in combination with 1L standard therapies within a subset of patients (pts) with mCRC. CheckMate 9X8 evaluated NIVO + mFOLFOX6/BEV vs mFOLFOX6/BEV in 1L mCRC (NCT03414983). Methods: Adults with previously untreated, unresectable, mCRC were randomized 2:1 to NIVO 240 mg + mFOLFOX6/BEV Q2W (NIVO + standard-of-care [SOC]) or mFOLFOX6/BEV Q2W (SOC). Primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1.1. Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), overall survival (OS), and safety. Results: 195 pts were randomized to NIVO + SOC (n = 127) or SOC (n = 68). Median (range) follow-up was 23.7 (0–33.2) months (mo; NIVO + SOC) vs 23.2 (0–32.3) mo (SOC). Median (range) duration of therapy was 9.9 (0.1–31.8+) mo (NIVO + SOC) and 7.7 (0.1–26.7+) mo (SOC). The HR (95% CI) for PFS was 0.81 (0.53–1.23; P = 0.30), which did not meet the prespecified threshold for statistical significance (median PFS, 11.9 mo in both arms; Table). PFS rates after 12 mo were higher with NIVO + SOC vs SOC (Table). ORR was 60% (NIVO + SOC) and 46% (SOC; odds ratio 1.72 [95% CI 0.96–3.10]) and median (95% CI) DOR was 12.9 (9.0–13.1) mo (NIVO + SOC) and 9.3 (7.5–11.3) mo (SOC; Table). Rates of grade 3−4 treatment-related adverse events (TRAEs) were higher with NIVO + SOC; however, no new safety signals were identified (Table). Biomarker analyses, including tumor mutational burden and baseline CD8 levels, will be presented. Conclusions: The primary endpoint of PFS was not met; however, NIVO + SOC showed higher PFS rates after 12 mo, a higher response rate, and more durable responses compared with SOC, along with acceptable safety, in 1L mCRC. Clinical trial information: NCT03414983. [Table: see text]

Abstract INTRODUCTION: Oncogenic FGFR2 alterations (fusions/rearrangements, amplifications, mutations) are key drivers in cholangiocarcinoma (CCA) and multiple solid tumors. Current pan-FGFR inhibitor (FGFRi) therapy is limited by off-isoform toxicity and acquired FGFR2 kinase domain resistance mutations. RLY-4008 is a highly selective and potent oral inhibitor designed to target both FGFR2 driver and resistance mutations. We initiated a first-in-human study in advanced solid tumors patients (pts) to define the safety, pharmacokinetics (PK) and efficacy of RLY-4008 (NCT04526106). METHODS: Adult pts received RLY-4008 QD or BID on a 4-week cycle following a BOIN escalation design. Adverse events (AEs), PK, ctDNA and anti-tumor activity (RECIST 1.1) were assessed. RESULTS: As of 16AUG21, 45 pts (35 CCA; 10 other) have been treated with RLY-4008 at total daily doses of 30-200 mg (18 pts BID; 27 pts QD). 44 pts had oncogenic FGFR2 alterations (26 fusions/13 mutations/5 amplifications). The median number of prior anti-neoplastic therapies was 3 (range 1-15). 94% (33/35) of CCA pts had prior chemotherapy and 69% (24/35) had prior FGFRi. 56% (9/16) CCA pts with prior FGFRi and evaluable ctDNA had ≥1 FGFR2 resistance mutation at baseline, most commonly at positions 549 (8/9), 617 (3/9), or 564 (2/9). RLY-4008 had rapid absorption (Tmax 1-7h), half-life to support QD dosing (18-34 h), dose-dependent exposure (AUC; Cmax) and predicted FGFR2 occupancy &gt;85% across dose levels. The MTD has not been defined, and QD dose exploration continues to select the optimal biologically efficacious dose. AEs occurring in &gt;20% of pts include stomatitis (49%), palmar-plantar erythrodysesthesia (PPE, 38%), dry mouth (29%), and nail toxicities (22%), majority of which were ≤Gr 2. 6 pts had Gr 1-2 retinopathy, which resolved in all cases. 5 AEs were considered dose limiting toxicities: 4 in BID (rash/PPE/mucositis/hyperbilirubinemia) and 1 in QD (retinopathy). No Gr 4/5 drug-related AEs were seen. 25 pts remain on treatment (range 1-37 weeks). RLY-4008 showed broad anti-tumor activity across dose levels and FGFR2 alterations with radiographic tumor reductions of ≥10% in 59% pts (19/32; -11% to -83%). Activity was seen in FGFRi-naïve, FGFR2-fusion+ CCA with PRs in 50% of pts (3/6, 2 confirmed and 1 pending confirmation; -56% to -83%). Activity was also seen in FGFRi pre-treated FGFR2-fusion+ CCA pts (N=16) with 16 SD, including 9 pts with tumor reduction ≥10% (from -12% to -35%). Of the FGFRi pre-treated FGFR2-fusion+ CCA patients with detectable FGFR2 resistance mutations in ctDNA at baseline, 78% (7/9) were undetectable at C2D1. CONCLUSION: RLY-4008 demonstrates promising safety, tolerability, and clinical activity in FGFR2-altered solid tumor pts, including those who progressed on prior FGFRi therapy. Consistent with the FGFR2-selective mechanism, minimal off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) was seen. These encouraging data validate selective targeting of FGFR2 and suggest that RLY-4008 has potential to overcome resistance to FGFRi. Citation Format: Lipika Goyal, Mitesh Borad, Vivek Subbiah, Amit Mahipal, Suneel Kamath, Kabir Mody, Robin Katie Kelley, Richard Kim, Vaibhav Sahai, Anthony El-Khoueiry, Efrat Dotan, Oleg Schmidt-Kittler, Jinshan Shen, Kai Yu Jen, Alicia Deary, Wei Guo, Mahesh Padval, Cori Ann J. Sherwin, Charles Ferte, Beni Wolf, Alison M. Schram. First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-02.

Abstract Background: Despite the promise of targeted agents in hematology, the high price of cancer therapies is a rapidly evolving problem. Until now, the increase in price of targeted anti-cancer treatments used in common hematological malignancies has not been evaluated. Here, we report patterns in price changes from 2015-2019 for multiple in-class anticancer medications for common hematologic malignancies. Methods: We utilized the publicly available Medicare Part D provider utilization and payment database from 2015 to 2019. We extracted drug prices (using generic names) for commonly used targeted anticancer agents for acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell lymphomas, and multiple myeloma. The primary outcome was the correlation of average change in Medicare spending per dosage unit among the multiple brand-name medications within each class available. We additionally calculated compound annual growth rates (CAGRs) [i.e. mean annual growth rates over a specified period of time] for medication costs within each class, and compared it with the consumer price index (CPI) (a measure of the average change over time in the prices of consumer items) and inflation rate. Agents without in-class competitor were excluded. CPI and inflation rates came from U.S. Bureau of Labor Statistics. Results: The study included 6 BCR-ABL inhibitors (1 generic), 2 BTK inhibitors, 2 IDH inhibitors, 2 FLT3 inhibitors, 3 IMIDs, 3 PI, 2 PI3K inhibitors, and 5 anti-CD20 monoclonal antibodies. The median (range) Pearson correlation coefficient values for drugs within each class were -0.155 (-0.984-0.992) for BCR-ABLi, -0.362 for BTKi, 0.234 (0.215-0.999) for IMIDs, 0.899 (-0.034-0.988) for PIs, and 0.954 (0.847-0.999) for anti-CD20 antibodies. The median correlation coefficient for BCR-ABLi was 0.751 if generic imatinib was excluded. The correlation coefficient between 2 nd and 3 rd generation IMIDs was 0.999. Non-generic BCR-ABLi and anti-CD20 antibodies showed strong linear association in price increase between two drugs within the same class. Due to drug novelty, coefficient could not be calculated for therapies with 2 or fewer data points (midostaurin, gilteritinib, enasidenib, ivosidenib, idelalisib, duvelisib). There was no significant correlation between expenditure for BTKi, PIs, and IMIDs. The median CAGRs in costs over this 5-year period were: were 6.29% for BCR-ABLi, 18.36% for BTKi, 2.69% for IDHi, 4.23% for FLT3i, 10.63% for IMIDs, 5.11% for PIs, 5.79% for PI3Ki, and 5.85% for anti-CD20s. The median CAGR in costs for modern precision-driven cancer therapeutic classes outpaced CPI (2.26%/year), and the average inflation rate (1.90%/year). Conclusions: Increase in cost within the same class should be weighed against incremental clinical benefit for the patients. For non-generic BCR-ABLi and anti-CD20 antibodies, despite there being several agents, the rise in drug expenditures correlated closely, calling into question the true value of within-class competition. There is an urgent need for drug pricing reform given the average expenditure of Medicare part D, and ultimately out-of-pocket costs for our patients with cancer continues to trend upwards. Increased advocacy efforts are needed to ensure precision therapeutics remains an attainable and sustainable goal. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Prostate‐specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68Ga‐PSMA‐11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68Ga‐PSMA‐11 PET was prospectively performed in patients with treatment‐naïve HCC on a digital PET scanner using cyclotron‐produced 68Ga. Uptake was graded qualitatively and semi‐quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor‐associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10‐5) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = −0.753; P = 1.58 × 10‐6). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68Ga‐PSMA‐11 standardized uptake value: SUVmax (median [range] 9.2 [4.9‐28.4]), SUVmean 4.7 (2.4‐12.7), and tumor‐to‐liver background ratio 2 (1.1‐11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68Ga‐PSMA‐11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

85 Background: Females are thought to be underrepresented in clinical trials, which may lead to care disparities. We characterized female enrollment trends in U.S. oncology trials registered on ClinicalTrials.gov and identified features associated with accurate representation. Methods: We employed a cross-sectional study design with descriptive, logistic regression, and cox regression analyses. We downloaded 270,172 studies registered on the Aggregate Analysis of the ClinicalTrials.gov database from October 1, 2008 to March 9, 2020, excluding non-interventional and reproductive organ specific trials. We then applied cancer/oncology specific Medical Subject Heading terms and manually reviewed the remaining 27,521 trials for true oncology content. Prevalence-corrected estimates for female participation were calculated as the percentage of females among trial participants divided by the percentage of females in the disease population per U.S. Surveillance, Epidemiology, and End Results Program (SEER) data (participation to prevalence ratio [PPR]), with a range between 0.8 and 1.2 reflecting accurate female representation in the trial. Results: Of 26,894 trials meeting eligibility criteria, 9,059 trials were completed in the U.S., 2,499 trials reported completed study status, and only 1,256 trials reported sex. Among 1,256 oncology trials and 229,056 participants, overall female representation was 46.9% (95% CI, 45.4-48.4%). 43% of trials were industry funded, 29% academic, and 28% U.S. government. Females were underrepresented compared to their disease burden in anal canal (PPR 0.21), thyroid (PPR 0.57), stomach (PPR 0.68), kidney (PPR 0.77), and bone (PPR 0.79) cancer trials. They were accurately represented in head and neck (PPR 0.80), lung (PPR 0.84), bladder (PPR 0.85), skin (PPR 0.88), pancreas (PPR 0.88), colon (PPR 0.90), hematologic (PPR 0.91), liver (PPR 1.01), CNS (PPR 1.03), soft tissue (PPR 1.05), and esophagus (PPR 1.05) cancer trials. Accurate representation was significantly associated with industry funding and pancreas cancer trial focus, but not associated with trial type (medical, surgical, radiation, other invasive, other) (Table). Conclusions: Females are underrepresented compared to their disease burden in many solid tumor clinical trials. Stakeholders can look to industry funded and pancreas cancer trials as models of improvement, but must increase female representation in clinical trials to improve cancer care. [Table: see text]