O’Dwyer, Peter J.

Abstract Background Adjuvant 5-FU monotherapy was previously the standard treatment for stage II/III rectal cancer. This study compared adjuvant FOLFIRI, FOLFOX, and 5-FU/LV. Methods Eligible patients had T3-T4 N0 or Tany N1-3 rectal adenocarcinoma ≤12 cm from the anal verge and received pre-operative or postoperative 5-FU chemoradiotherapy (CRT). Patients were randomized to adjuvant FOLFIRI (8 cycles), FOLFOX (8 cycles), or 5-FU/LV weekly (6/8 weeks; 3 cycles). The trial planned to enroll 3,150 patients but was closed early following activation of an alternative adjuvant rectal cancer study including bevacizumab (E5204). The primary endpoint was overall survival (OS); secondary endpoints included disease-free survival (DFS), sphincter preservation, tolerability, and quality of life (QOL). Results The trial enrolled 225 patients (179 randomized) before early closure. Grade 3/4 toxicity occurred in 59%, with neutropenia, leukopenia, and diarrhea being the most common. At a median follow-up of 9.7 years, no significant OS or DFS differences were observed. The rate of sphincter preservation was numerically higher with FOLFIRI and FOLFOX versus 5-FU/LV, but the difference was not statistically significant. Conclusion FOLFOX and FOLFIRI can be safely administered after CRT in rectal cancer patients safely with expected toxicities. Due to early trial closure and small sample size, the survival analysis was underpowered to detect a significant difference between regimens. ClinicalTrials.gov identifier NCT00068692

Abstract Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First-generation trials like NCI-MATCH (Molecular Analysis for Therapy Choice) have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single-agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target. As such, newer approaches employing combinations of targeted therapy, or targeted therapy with standard therapies, need to be considered. The NCI has recently embarked on three second-generation precision medicine trials to address this need: ComboMATCH, iMATCH, and myeloMATCH. The design of these trials and necessary infrastructure are discussed in the following perspective.

Purpose Colorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer. Patients and Methods Eight hundred twenty-nine metastatic colorectal cancer patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to one of three treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was overall survival, with additional determinations of progression-free survival, response, and toxicity. Results The median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for death = 0.75; P = .0011), and 10.2 months for those treated with bevacizumab alone. The median progression-free survival for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for progression = 0.61; P < .0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively ( P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison). Bevacizumab was associated with hypertension, bleeding, and vomiting. Conclusion The addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin improves survival duration for patients with previously treated metastatic colorectal cancer.

PURPOSE In the United States, the National Cancer Institute National Cancer Clinical Trials Network (NCTN) groups have conducted publicly funded oncology research for 50 years. The combined impact of all adult network group trials has never been systematically examined. METHODS We identified randomized, phase III trials from the adult NCTN groups, reported from 1980 onward, with statistically significant findings for ≥ 1 clinical, time-dependent outcomes. In the subset of trials in which the experimental arm improved overall survival, gains in population life-years were estimated by deriving trial-specific hazard functions and hazard ratios to estimate the experimental treatment benefit and then mapping this trial-level benefit onto the US cancer population using registry and life-table data. Scientific impact was based on citation data from Google Scholar. Federal investment costs per life-year gained were estimated. The results were derived through December 31, 2020. RESULTS One hundred sixty-two trials comprised of 108,334 patients were analyzed, representing 29.8% (162/544) of trials conducted. The most common cancers included breast (34), gynecologic (28), and lung (14). The trials were cited 165,336 times (mean, 62.2 citations/trial/year); 87.7% of trials were cited in cancer care guidelines in favor of the recommended treatment. These studies were estimated to have generated 14.2 million (95% CI, 11.5 to 16.5 million) additional life-years to patients with cancer, with projected gains of 24.1 million (95% CI, 19.7 to 28.2 million) life-years by 2030. The federal investment cost per life-year gained through 2020 was $326 in US dollars. CONCLUSION NCTN randomized trials have been widely cited and are routinely included in clinical guidelines. Moreover, their conduct has predicted substantial improvements in overall survival in the United States for patients with oncologic disease, suggesting they have contributed meaningfully to this nation's health. These findings demonstrate the critical role of government-sponsored research in extending the lives of patients with cancer.

4020 Background: High grade (G3) GEPNENs are a rare and heterogeneous disease entity for which there is little prospective treatment data. EP chemotherapy is the treatment standard but this may not be appropriate for all G3 GEPNEN pts. CAPTEM has demonstrated activity in G3 GEPNENs and may be a promising alternative. EA2142 aimed to determine if CAPTEM was superior to EP in pts with G3 GEPNENs. Methods: This was a multicenter, randomized (1:1) phase II trial for pts with a locally advanced and unresectable or metastatic well differentiated G3 neuroendocrine tumor (NET) or a poorly differentiated, non-small cell G3 neuroendocrine carcinoma (NEC) of suspected gastrointestinal origin and an ECOG PS of 0-2. Pathology must have demonstrated a Ki-67 of 20-100% or at least 10 mitoses/10 high powered field. Pts were randomized to receive capecitabine 750 mg/m2 orally every 12 hours on days 1-14 and temozolomide 200 mg/m2 orally once daily on days 10-14 of a 28-day treatment cycle (Arm A) or etoposide 100 mg/m2 daily on days 1-3 with either cisplatin 25 mg/m2 daily on days 1-3 or carboplatin AUC 5 on day 1 of a 21-day treatment cycle (Arm B). Restaging scans were performed every 8 weeks and toxicity monitored per CTCAEv4. Final statistical plan was to accrue 80 pts to detect a 67% improvement in progression free survival (PFS) (primary endpoint) with CAPTEM as compared to EP, 80% power and one-sided significance level of 0.10. A planned interim analysis for efficacy and futility was conducted. Results: A total of 67 pts were enrolled (Arm A, n=32; Arm B, n=35). Male 58%, African American 4%, Asian 3%. Mean age 61. Among 63 eligible pts, primary tumor site pancreatic 56%, non-pancreatic 43%. Poorly differentiated 57%, well differentiated 33%, unknown 10%. Mean Ki-67 48% (Arm A), 60% (Arm B). The study was closed prior to full accrual due to futility at 57.7% information time. In the interim analysis, among 62 eligible pts, PFS, overall survival and response rate with CAPTEM were 2.43 months (mos) (95% CI 2.04, 7.72), 12.6 mos, 9% respectively vs 5.36 mos (95% CI 2.14, 7.23), 13.6 mos and 10% with EP. Toxicity was evaluable in 57 pts with Grade (G) 3/4 events occurring in 29% of pts on Arm A, 66% of pts on Arm B. G3/4 events occurring in more than 5% of pts on Arm A—febrile neutropenia (n=2); abdominal pain (n=2); diarrhea (n=2); nausea (n=2); neutropenia (n=2); dehydration (n=2) and on Arm B—anemia (n=8); febrile neutropenia (n=2); fatigue (n=2); lymphopenia (n=2); neutropenia (n=12); thrombocytopenia (n=4); leukopenia (n=6). There was one G5 event on Arm A due to sepsis. Conclusions: CAPTEM does not appear to be superior to EP chemotherapy as front-line treatment for pts with G3 NENs but does demonstrate a more favorable toxicity profile. Studies assessing G3 NET independently of G3 NEC are needed. Clinical trial information: NCT02595424.

PURPOSE NCI-MATCH is a nationwide, histology-agnostic, signal-finding, molecular profile–driven trial for patients with refractory cancers, lymphomas, or myelomas. Patients with tumors harboring actionable aberration(s) in fibroblast growth factor receptor ( FGFR) 1-3 were treated with AZD4547, an oral FGFR1-3 inhibitor. METHODS Patients’ tumors were screened by next-generation sequencing for predefined FGFR amplification, activating mutations, or fusions. Patients were treated with AZD4547, 80 mg orally twice daily until progression of disease or drug intolerance. A response rate of 16% was considered promising. RESULTS Between July 2016 and June 2017, 70 patients were assigned and 48 received protocol therapy and are eligible for analysis. Patients’ tumors harbored FGFR1 or FGFR2 amplification (n = 20), FGFR2 or FGFR3 single-nucleotide variants (n = 19), or FGFR1 or FGFR3 fusions (n = 9). The most common primary tumors were breast (33.3%), urothelial (12.5%), and cervical cancer (10.4%).Grade 3 adverse events were consistent with those described in previous clinical trials. Confirmed partial responses were seen in 8% (90% CI, 3% to 18%) and were observed only in patients whose tumors harbored FGFR1-3 point mutations or fusions. Stable disease was observed in 37.5% (90% CI, 25.8% to 50.4%). The median progression-free survival (PFS) was 3.4 months, and the 6-month PFS rate was 15% (90% CI, 8% to 31%). For patients with tumors harboring FGFR fusions, the response rate was 22% (90% CI, 4.1% to 55%), and 6-month PFS rate was 56% (90% CI, 31% to 100%). CONCLUSION Preliminary signals of activity appeared to be limited to cancers harboring FGFR activating mutations and fusions, although AZD4547 did not meet the primary end point. Different FGFR somatic alterations may confer different levels of signaling potency and/or oncogene dependence.

e14711 Background: Postoperative adjuvant chemotherapy has been historically limited to single agent 5FU in stage II/III rectal cancer pts. This phase III trial evaluated differences between pts treated with adjuvant FOLFOX versus FOLFIRI versus FU alone in stage II/III rectal cancer. Methods: Eligibility: resectable (T3-4 N0,Tany N1-3) adenocarcinoma rectum ≤12cm from anal verge. Pts had the option to receive FU with pre or postoperative XRT (50.4Gy). Preoperative FU/XRT pts were randomized to adjuvant FOLFIRI (arm A), FOLFOX (arm B), FU/LV(arm C). Postoperative FU/XRT pts were randomized to adjuvant FOLFIRI (arm D), FOLFOX (arm E), FU/LV (arm F). Pts received 8 cycles. Overall survival (OS) was the primary endpoint. Secondary endpoints included toxicity, sphincter preservation and patterns of failure. Results: 225pts out of planned 3150 were enrolled (10/03 to 10/05). Data Monitoring Committee closed E3201 when the GI Intergroup developed an alternative trial with bevacizumab (E5204). 179 pts were randomized; (A:28, B:25, C:30, D:31, E:33, F:32). There was increased grade 3/4 toxicity, mainly diarrhea,in postoperative FU/XRT arms (D:39%), (E:28%), (F:48%). Twenty-two (12%) pts did not receive adjuvant therapy. At a median follow up of 7.4yrs, the five-year recurrence free rate was 69%. Median OS was 8.3 yrs. There was no statistical difference in OS between all randomized groups. Five-year OS in arms (A:B:C:D:E:F) were (73%, 83%, 83%, 73%, 78%, 73%) respectively. Conclusions: FOLFOX can be safely administered to rectal cancer pts following chemo radiation. Given limitations of early trial closure and small sample size, there was no difference in OS between pts who received FU alone, oxaliplatin based or irinotecan based adjuvant therapy. Clinical trial information: NCT00068692.

LBA4004 Background: Gemcitabine (GEM) is the cornerstone of treatment of metastatic pancreatic cancer (PANCA). FDR GEM or GEMOX are promising, but have yet to convincingly demonstrate a survival advantage over GEM alone. E6201 compares overall survival (OS) of standard GEM 1000 mg/m2/30 min wkly ×7 over 56 days then wkly ×3 q28 d (ARM A) vs. FDR GEM 1500 mg/m2/150 min wkly ×3 q28 days (ARM B) or GEM 1000 mg/m2/100-min/d1 + oxaliplatin 100 mg/m2/d2 q14d (ARM C). Secondary endpoints are the comparison of the experimental regimens, toxicity, response, patterns of failure, progression-free survival and quality-of-life. Methods: This multi-institutional trial included patients (pts) with measurable and non-measurable advanced, unresectable PAN CA, normal organ function and PS 0–2. Pts were chemonaive, although prior adjuvant radiosensitizing 5FU was permitted. Pts were stratified by PS 0–1 vs 2 and locally advanced vs metastatic disease The study was designed to detect a 33% difference in median survival (hazard ratio 1.33) with 81% power while maintaining a significance level of 2.5% in a two-sided test for each of the two primary comparisons, assuming exponential failure and median survival of 6 mo for Arm A and 8 mo for Arm B and C (N = 750 eligible). Results: Accrual started in 3/03 and completed in 3/05. Median follow up is 5.8 mo. 833 pts (53% men; 88% PS 0–1; 88% metastatic), were randomized with 280, 277 and 276 pts in Arms A, B and C. The third interim analysis was conducted with 89.5% information on 3/2006. The predominant toxicity, available for 758 pts, was grade 3/4 myelosuppression and fatigue. Two deaths from ARDS and infection occurred. Median OS for ARMS A, B, and C are 4.96, 6.01 and 6.47 months, respectively. Hazard ratio A vs B is 1.21 with stratified log rank of 0.053 and for A vs C is 1.22 with stratified log rank of 0.045, neither statistically significant. Conclusion: E6201 final OS results will be available in June, 2006. [Table: see text] [Table: see text]

Abstract Background The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group and the National Cancer Institute, was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology. Methods Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, and enrollment rates as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational next-generation DNA–targeted sequencing assay of alterations in 143 genes, and protein expression of protein expression of phosphatase and tensin homolog, mutL homolog 1, mutS homolog 2, and RB transcriptional corepressor 1. Treatments were allocated with a validated computational platform (MATCHBOX). A preplanned interim analysis evaluated assumptions and feasibility in this novel trial. Results At interim analysis, accrual was robust, tumor biopsies were safe (&lt;1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments, and improved assay throughput and efficiency (93.9% completion and 14-day turnaround). Conclusions The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients.

AbstractBackgroundThe addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum.Subjects, Materials, and MethodsPatients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles.ResultsE5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3–4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue.ConclusionAt 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer.Implications for PracticeAt 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.