Background: KRAS p.G12C mutation is an oncogenic driver occurring in 1e3% of gastrointestinal (GI) cancers. AMG 510 is a first-in-class small molecule inhibitor of KRAS G12C. Previously, AMG 510 demonstrated a favorable tolerability profile and preliminary efficacy in the phase 1, first-in-human trial involving patients with advanced solid tumors harboring KRAS p.G12C. In this updated report, we present data in a subset of patients with advanced colorectal cancer (CRC) or other GI cancers.Methods: Key inclusion criteria: KRAS p.G12C mutation identified through molecular testing, measurable disease, and prior systemic anticancer therapy. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), as assessed per RECIST 1.1, and overall survival (OS). Oral daily doses of 180, 360, 720, and 960 mg were evaluated in dose escalation, and 960 mg was selected for dose expansion. Response was assessed every 6 weeks for 24 weeks then every 12 weeks thereafter.Results: As of the data cutoff of Jan 8, 2020, 59 patients (25 [42.4%] female), including 42 with CRC and 17 with other GI cancers (10 pancreatic cancer, 4 appendiceal cancer, 1 bile duct cancer, 1 small bowel cancer, and 1 esophageal cancer), were enrolled and dosed. The median age was 58 years (range: 33e82).Patients received a median of 3 (range: 1e4) prior lines of therapy, with 24 patients (40.7%) receiving > 3 prior lines. Median follow-up time was 7.7 months (range: 1.2e 15.9). Of all 59 patients, 17 patients (28.8%) died, and 16 patients (27.1%) remained on treatment. The most common reason for treatment discontinuation was disease progression. 28 (47.5%) and 10 (16.9%) patients had remained on treatment for more than 3 and 6 months, respectively. Treatment-related adverse events (TRAEs) occurred in 27 patients (45.8%), most of whom had grade 1/2 TRAEs. 3 patients (5.1%) had grade 3 TRAEs, including diarrhea (3.4%) and anemia (1.7%). No doselimiting toxicities, fatal/grade > 3 TRAEs, or TRAEs leading to treatment discontinuation were reported. All 42 patients with CRC had been followed up by at least 7 weeks and were evaluable for response. ORR and DCR were 7.1% (3/42, all confirmed) and 76.2% (32/42), respectively. In patients with CRC receiving the 960 mg dose, ORR and DCR were 12.0% (3/25) and 80.0% (20/25). 15 of 17 patients with other GI cancers were evaluable: 1 had confirmed partial response (appendiceal), 9 had stable disease (6 pancreatic, 2 appendiceal, and 1 bile duct), and 5 had progressive disease (2 progressed before the 1 st postbaseline assessment). 3 patients with pancreatic cancer achieving stable disease had the best tumor burden reduction of 28.0%, 28.9%, and 31.6% from baseline, respectively. PFS/OS will be reported at the congress. Conclusion:In patients with heavily pretreated KRAS p.G12C mutant GI cancers, AMG 510 monotherapy was well tolerated, with the majority of patients achieving disease control. The study is ongoing. (clinical trial informat...
Background: Low muscle mass (quantity) is common in patients with advanced cancer, but little is known about muscle radiodensity (quality). We sought to describe the associations of muscle mass and radiodensity with symptom burden, healthcare use, and survival in hospitalized patients with advanced cancer. Methods: We prospectively enrolled hospitalized patients with advanced cancer from September 2014 through May 2016. Upon admission, patients reported their physical (Edmonton Symptom Assessment System [ESAS]) and psychological (Patient Health Questionnaire-4 [PHQ-4]) symptoms. We used CT scans performed per routine care within 45 days before enrollment to evaluate muscle mass and radiodensity. We used regression models to examine associations of muscle mass and radiodensity with patients’ symptom burden, healthcare use (hospital length of stay and readmissions), and survival. Results: Of 1,121 patients enrolled, 677 had evaluable muscle data on CT (mean age, 62.86 ± 12.95 years; 51.1% female). Older age and female sex were associated with lower muscle mass (age: B, –0.16; P<.001; female: B, –6.89; P<.001) and radiodensity (age: B, –0.33; P<.001; female: B, –1.66; P=.014), and higher BMI was associated with higher muscle mass (B, 0.58; P<.001) and lower radiodensity (B, –0.61; P<.001). Higher muscle mass was significantly associated with improved survival (hazard ratio, 0.97; P<.001). Notably, higher muscle radiodensity was significantly associated with lower ESAS-Physical (B, –0.17; P=.016), ESAS-Total (B, –0.29; P=.002), PHQ-4-Depression (B, –0.03; P=.006), and PHQ-4-Anxiety (B, –0.03; P=.008) symptoms, as well as decreased hospital length of stay (B, –0.07; P=.005), risk of readmission or death in 90 days (odds ratio, 0.97; P<.001), and improved survival (hazard ratio, 0.97; P<.001). Conclusions: Although muscle mass (quantity) only correlated with survival, we found that muscle radiodensity (quality) was associated with patients’ symptoms, healthcare use, and survival. These findings underscore the added importance of assessing muscle quality when seeking to address adverse muscle changes in oncology.
391 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer. Immunotherapy (IO) has shown minimal activity. In preclinical models, radiation (XRT) increases likelihood of response to IO via an abscopal effect where local tx (treatment) of a tumor leads to an antitumor response distantly, with synergy between XRT and dual checkpoint blockade. In this study, we assessed CTLA-4 and PD-1 blockade with XRT as a strategy to stimulate an immune response for patients (pts) with PDAC. Methods: In this open-label, single arm phase-2 study, we enrolled 25 metastatic PDAC pts in an exploratory cohort. Eligible pts had histologically-confirmed PDAC, ECOG PS 0-1, and progression on at least 1 line of tx. Tx consisted of Ipilimumab (1 mg/kg every 6 wks), Nivolumab (240 mg every 2 wks) and 3 fractions of 8 Gy of XRT at cycle 2. Tx continued until PD, discontinuation or withdrawal. Endpoints include Disease Control Rate (DCR), ORR, PFS, OS and safety. Radiological evaluations were every 3 months. Response was defined as disease control outside of the radiation field. We obtained serial tumor biopsies pre-tx, during checkpoint blockade alone and 2 weeks after XRT. Intention to treat analysis includes all pts receiving at least one dose of study tx. Results: 22 pts were enrolled and evaluable from 6/2017-6/2018, median age 60 years (32-75), 73% male and 100% MSS. DCR was 27% and ORR was 14% with 1 pt having a complete response. All responses were out of the radiation field. Median PFS was 76 days in the entire cohort; 163 days for pts with disease control vs 62.5 days for pts with PD or who came off study prior to initial imaging. 7 pts did not receive XRT due to clinical progression. Treatment-related adverse events (AEs) were reported in 12/22 pts (54.5%). 8/22 pts (36.4%) experienced grade ≥ 3 toxicities. Elevated lipase, lymphopenia, fatigue, hyperglycemia, mucositis and hepatitis were the most common AEs. 1/22 (4.5%) pt had a grade 5 AE possibly related to tx. Conclusions: Dual blockade of CTLA-4 and PD-1 with XRT is feasible and demonstrates promising activity in pts with metastatic PDAC. We will report the updated efficacy and safety data as well as outcomes from the correlative serial biopsies upon completion. Clinical trial information: NCT03104439.
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