Citations

5062 Background: Inflammation has been linked to prostate cancer (PCa) progression which may be mediated by the transcription factor nuclear factor kappa B (NFκB). Using a bioinformatic screen focused on NFκB pathway activation in lethal PCa, we identified the tumor suppressor ZFP36 as a key node of the NFκB network. We also showed in vitro that ZFP36 expression was inversely associated with both NFκB-controlled gene levels and proliferation and sensitivity to enzalutamide. We examined the role of ZFP36 and PCa progression in patient cohorts. Methods: The association between low mRNA expression of ZFP36 (levels in the lower quartile) and lethal PCa (defined as metastatic disease or death) was assessed with logistic regression among men with localized PCa in two independent cohorts treated with radical prostatectomy (RP). The discovery cohort was RP samples from Health Professional Follow-up Study and Physicians Health Study and the validation cohort was RP samples from Cleveland Clinic, Mayo Clinic, Johns Hopkins and MSKCC. In a third cohort from Cornell University, ZFP36 expression levels were assessed in RP samples from patients with localized PCa and biopsies of metastatic castration resistant prostate cancer (mCRPC). Results: Table 1 shows men with localized PCa and lower quartile of tumor ZFP36 expression had a nearly 2-fold higher risk of lethal PCa after adjusting for known clinical and histological prognostic features (age, RP Gleason score, T-stage); an association confirmed in the validation cohort. ZFP36 gene expression was also significantly lower in mCRPC (n=53) compared with a localized RP cohort (n=68) (p-value <0.0001). Conclusions: In humans lower ZFP36 in RP specimens is associated with clinically significant risk of lethal PCa after treatment with curative intent and lower ZFP36levels are found in metastatic tissue. [Table: see text]

TPS3624 Background: To improve survival for patients with mCRC, efforts are needed to identify and treat actionable genomic alterations. HER2 is amplified in approximately 5-8% of patients with KRAS and NRAS (RAS) wild-type mCRC. HER2 functions as an oncogenic driver and a mediator of EGFR antibody (Ab) resistance. Although prior studies have shown that anti-HER2 therapies are active in patients with HER2+ (HER2 IHC 3+ or HER2 amplified) mCRC, there are no HER2-directed therapies approved for these patients. Tucatinib is a potent and highly selective oral small molecule tyrosine kinase inhibitor of HER2, currently being developed to treat metastatic breast cancer. In HER2+ CRC patient derived xenograft models, tucatinib has substantial anti-tumor activity. The addition of the anti-HER2 monoclonal Ab trastuzumab augments tumor growth inhibition. Methods: This single-arm phase II study will test the combination of tucatinib and trastuzumab in patients with HER2+ mCRC. Eligible patients include those with RAS wild-type mCRC who have been previously treated with 5-FU, oxaliplatin, irinotecan, and an anti-VEGF monoclonal Ab. Patients must have HER2+ disease by IHC, FISH, or NGS. Prior treatment with anti-HER2 targeting therapy is excluded. The primary objective is to assess the objective response rate for the combination. Secondary objectives are to evaluate the efficacy (PFS, OS, clinical benefit rate), safety, and tolerability of the combination. Correlation between tissue and blood-based biomarkers and clinical outcomes will be explored. Blood will be collected at baseline and each restaging to determine if the combination eliminates HER2 amplified circulating tumor DNA. Subjects will receive tucatinib at a dose of 300mg by mouth daily, and trastuzumab will be administered every 3 weeks (8 mg/kg IV day 1 of cycle 1, then 6 mg/kg IV Q3 weeks). Response will be assessed every 3 cycles (9 weeks) per RECIST version 1.1. Both agents will be provided by the study. This study was initiated in February 2017. Recruitment is ongoing at 8 sites in the Academic and Community Cancer Research United (ACCRU) network. Clinical trial information: NCT03043313.

3551 Background: Cutaneous toxicity is a known adverse effect of multikinase inhibitors and has been associated with clinical outcomes (Granito 2016). In the phase 3 CORRECT trial (NCT01103323), the multikinase inhibitor regorafenib significantly improved overall survival (OS) vs placebo in patients with mCRC (hazard ratio [HR] 0.77, 95% CI 0.64, 0.94; 1-sided P = 0.0052). This retrospective analysis explored whether HFSR was associated with outcomes in CORRECT. Methods: Patients randomized to receive regorafenib 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether or not they had HFSR. Estimates of OS and progression-free survival (PFS) (95% CI) were calculated using the Kaplan–Meier method. Patients who were randomized, but not treated, were included in the no HFSR group for the analysis of survival. Results: Of the 505 randomized patients, 500 received at least one dose of regorafenib. Among the treated patients, 47% (n = 235) had HFSR of any grade and 17% (n = 83) had HFSR grade 3. Of the patients who had HFSR, 69% (n = 162) had their first HFSR event (any grade) during the first treatment cycle. There was some imbalance in baseline characteristics between groups (Table). Survival was improved in patients who had HFSR at any time vs those who did not (Table). The OS benefit was also observed in patients who had the first HFSR event during Cycle 1 vs those who did not (median OS 7.2 vs 5.7 months; HR 0.66, 95% CI 0.51, 0.87). Conclusions: This post-hoc exploratory analysis suggests that patients who had HFSR had a greater treatment benefit from regorafenib. Since HFSR and survival are post-baseline assessments, results may be confounded by baseline factors or other unknown factors. Clinical trial information: NCT01103323. [Table: see text]

3034 Background: Unique to modern immune therapy for cancer is that early in the course of treatment, patients frequently exhibit transient tumor enlargement (pseudo-progression, pPROG) due to tumor infiltration by lymphocytes (TIL). Currently, pPROG cannot be reliably distinguished from true tumor progression (PROG). There is a need for biomarker techniques to discriminate pPROG (effect of therapy) and PROG (therapy failure). Nuclear medicine offers radiopharmaceuticals capable of imaging immune cells; images can be fused to evaluate functional and anatomic characteristics of tumors, and potentially discriminate pPROG from PROG. Methods: In our study of metastatic melanoma patients, SPECT/CT imaging with 99mTc-interleukin-2 (99mTc-IL2) was performed to visualize TIL. Images were collected before/after 12 weeks of ipilimumab (IPI) or pembrolizomab (PEMBRO) therapy. The 99mTc-IL2 tracer was synthesized by conjugating succinimidyl-6-hydrazinopyridine-3-carboxylate (HYNIC-NHS) with commercial interleukin-2 (Aldesleukin). HYNIC-IL2 was incubated with tricine, 99mTcO4- (370-740 MBq) and SnCl2. After labelling 99mTc-IL2 was purified by reverse-phase chromatography and diluted in 5% glucose with 0.1% human albumin before injection. Five patients were enrolled in this study. Two patients failed to complete the 12 week 99mTc-IL2 scan due to discontinuation of IPI after: 1) grade 3 colitis and 2) patient refusal for adverse events attributed to IPI. No adverse events attributable to the tracer infusion were reported. Results: Metastatic lesions could be visualized by the tracer. Some lesions decreased in size, while others increased. A positive correlation was found between size and 99mTc-IL2 uptake, before and after therapy, suggesting the potential discrimination of tumor PROG (no 99mTc-IL2 uptake) from pPROG (high 99mTc-IL2 uptake). Immunohistochemical staining for TIL of 99mTc-IL2 positive and negative lesions are illustrated. Conclusions: The results demonstrate feasibility of 99mTc-IL2 imaging as a clinically useful tool capable of discriminating tumor PROG from pPROG. A clinical validation study is in progress. Clinical trial information: NCT01789827.

Abstract Background In the phase III CORRECT trial, regorafenib significantly improved survival in treatment-refractory metastatic colorectal cancer (mCRC). The CONSIGN study was designed to further characterize regorafenib safety and allow patients access to regorafenib before market authorization. Methods This prospective, single-arm study enrolled patients in 25 countries at 186 sites. Patients with treatment-refractory mCRC and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoint was safety. Progression-free survival (PFS) per investigator assessment was the only efficacy evaluation. Results In total, 2,872 patients were assigned to treatment and 2,864 were treated. Median age was 62 years, ECOG PS 0/1 was 47%/53%, and 74% had received at least three prior regimens for metastatic disease. Median treatment duration was three cycles. Treatment-emergent adverse events (TEAEs) led to dose reduction in 46% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 9%. Grade 5 regorafenib-related TEAEs occurred in &lt;1%. The most common grade ≥3 regorafenib-related TEAEs were hypertension (15%), hand–foot skin reaction (14%), fatigue (13%), diarrhea (5%), and hypophosphatemia (5%). Treatment-emergent grade 3–4 laboratory toxicities included alanine aminotransferase (6%), aspartate aminotransferase (7%), and bilirubin (13%). Ongoing monitoring identified one nonfatal case of regorafenib-related severe drug-induced liver injury per DILI Working Group criteria. Median PFS (95% confidence interval [CI]) was 2.7 months (2.6–2.7). Conclusion In CONSIGN, the frequency and severity of TEAEs were consistent with the known safety profile of regorafenib. PFS was similar to reports of phase III trials. ClinicalTrials.gov: NCT01538680. Implications for Practice Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment-refractory mCRC in the phase III CORRECT (N = 760) and CONCUR (N = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events.