KEYSTEP-008: phase II trial of pembrolizumab-based combination in MSI-H/dMMR metastatic colorectal cancer.

Robust clinical activity has been observed with the immune checkpoint inhibitor pembrolizumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). However, given the response rate of 45% and a median progression-free survival of 16.5 months with first-line pembrolizumab demonstrated in KEYNOTE-177, there is room for improvement. Targeting a second immune receptor, such as CTLA-4, LAG-3, TIGIT, or ILT-4 may improve efficacy of PD-1 inhibition. Here we describe the design and rationale for the open-label, randomized, phase II KEYSTEP-008 trial, which will evaluate the efficacy and safety of pembrolizumab-based combination therapy compared with pembrolizumab monotherapy in chemotherapy-refractory (cohort A) or previously untreated (cohort B) MSI-H/dMMR mCRC. Clinical Trial Registration: NCT04895722 (ClinicalTrials.gov).

Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer.

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1-57.8) months with pembrolizumab and 43.9 (range 36.6-55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months-NR) with pembrolizumab versus 10.4 (95% CI 6.3-22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26-1.20). Median OS was NR (range 13.8 months-NR) versus 30.0 (14.7-NR) months (HR 0.65, 95% CI 0.27-1.55) and ORR was 50% (95% CI 28-72) versus 46% (95% CI 27-67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.

Association of Prediagnosis Obesity and Postdiagnosis Aspirin With Survival From Stage IV Colorectal Cancer.

Importance: The potential relationship between obesity and colorectal cancer (CRC) outcome is poorly understood in patients with late-stage disease. Increased body mass index may negate aspirin use for cancer prevention, but its role as a factor on the effectiveness of postdiagnosis aspirin use is unclear. Objective: To evaluate how prediagnosis obesity and postdiagnosis aspirin use may be associated with overall survival in patients with late-stage colorectal cancer. Design, Setting, and Participants: This cross-sectional study used self-reported data from patients with metastatic or treatment-refractory disease who consented to a clinical protocol at MD Anderson Cancer Center, a large US cancer treatment center. Patients were enrolled between 2010 and 2018 and followed up for mortality through July 2020. Analyses were conducted through March 2022. Exposures: Body mass index in the decade prior to initial diagnosis and regular aspirin use at survey completion. Main Outcomes and Measures: Overall survival was measured from stage IV diagnosis until death or last follow-up. Cox proportional hazards models were constructed to estimate associations of prediagnosis obesity and postdiagnosis aspirin use with overall survival. Results: Of 656 patients included in this analysis, 280 (42.7%) were women, 135 (20.6%) were diagnosed with CRC before age 45 years, 414 (63.1%) were diagnosed between ages 45 and 65 years, and 107 (16.3%) were diagnosed at 65 years or older; 105 patients (16.0%) were Black or Hispanic, and 501 (76.4%) were non-Hispanic White. Controlling for age, sex, race, stage at initial diagnosis, and weight change between prediagnosis and survey date, patients with obesity in the decade prior to CRC diagnosis had significantly higher likelihood of death (hazard ratio, 1.45; 95% CI, 1.11-1.91) compared with those with normal prediagnosis body mass index. Furthermore, only patients with normal prediagnosis body mass index experienced significant survival benefit with postdiagnosis aspirin use (hazard ratio, 0.59; 95% CI, 0.39-0.90). Conclusions and Relevance: In this cross-sectional study, our findings suggest potentially differential tumor development in the long-term physiologic host environment of obesity. Confirmation and further evaluation are needed to determine whether prediagnosis body mass index may be used to estimate the benefit from postdiagnosis aspirin use.

Single-Cell Sequencing Reveals Trajectory of Tumor-Infiltrating Lymphocyte States in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) has few effective treatments. Immunotherapy, an attractive alternative strategy, remains challenging with the lack of knowledge on the tumor-infiltrating lymphocyte (TIL) landscape in PDAC. To generate a reference of T-cell subpopulations, we profiled 80,000 T cells from 57 PDAC samples, 22 uninvolved/normal samples, and cultured TIL using single-cell transcriptomic and T-cell receptor analysis. These data revealed 20 cell states and heterogeneous distributions of TIL populations. The CD8+ TIL contained a putative transitional GZMK+ population based on T-cell receptor clonotype sharing, and cell-state trajectory analysis showed similarity to a GZMB+PRF1+ cytotoxic and a CXCL13+ dysfunctional population. Statistical analysis suggested that certain TIL states, such as dysfunctional and inhibitory populations, often occurred together. Finally, analysis of cultured TIL revealed that high-frequency clones from effector populations were preferentially expanded. These data provide a framework for understanding the PDAC TIL landscape for future TIL use in immunotherapy for PDAC. SIGNIFICANCE: To improve the efficacy of immunotherapy in PDAC, there is a great need to understand the PDAC TIL landscape. This study represents a reference of PDAC TIL subpopulations and their relationships and provides a foundation upon which to base future immunotherapeutic efforts. This article is highlighted in the In This Issue feature, p. 2221.

Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study.

BACKGROUND: Pembrolizumab has shown improved progression-free survival versus chemotherapy in patients with newly diagnosed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. However, the treatment's effect on overall survival in this cohort of patients was unknown. Here, we present the final overall survival analysis of the KEYNOTE-177 study. METHODS: This randomised, open-label, phase 3 study was done in 193 academic medical centres and hospitals in 23 countries. We recruited patients aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Patients were randomly assigned (1:1) in blocks of four using an interactive voice response system or integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to the investigator's choice of intravenous mFOLFOX6 (oxaliplatin 85 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1-2) or intravenous FOLFIRI (irinotecan 180 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1-2), every 2 weeks with or without intravenous bevacizumab 5 mg/kg every 2 weeks or intravenous weekly cetuximab (first dose 400 mg/m2, then 250 mg/m2 for every subsequent dose). Patients receiving chemotherapy could cross over to pembrolizumab for up to 35 treatment cycles after progression. The co-primary endpoints were overall survival and progression-free survival in the intention-to-treat population. KEYNOTE-177 is registered at ClinicalTrials.gov, NCT02563002, and is no longer enrolling patients. FINDINGS: Between Feb 11, 2016, and Feb 19, 2018, 852 patients were screened, of whom 307 (36%) were randomly assigned to pembrolizumab (n=153) or chemotherapy (n=154). 93 (60%) patients crossed over from chemotherapy to anti-PD-1 or anti-PD-L1 therapy (56 patients to on-study pembrolizumab and 37 patients to off-study therapy). At final analysis (median follow-up of 44·5 months [IQR 39·7-49·8]), median overall survival was not reached (NR; 95% CI 49·2-NR) with pembrolizumab vs 36·7 months (27·6-NR) with chemotherapy (hazard ratio [HR] 0·74; 95% CI 0·53-1·03; p=0·036). Superiority of pembrolizumab versus chemotherapy for overall survival was not demonstrated because the prespecified α of 0·025 needed for statistical significance was not achieved. At this updated analysis, median progression-free survival was 16·5 months (95% CI 5·4-38·1) with pembrolizumab versus 8·2 months (6·1-10·2) with chemotherapy (HR 0·59, 95% CI 0·45-0·79). Treatment-related adverse events of grade 3 or worse occurred in 33 (22%) of 153 patients in the pembrolizumab group versus 95 (66%) of 143 patients in the chemotherapy group. Common adverse events of grade 3 or worse that were attributed to pembrolizumab were increased alanine aminotransferase, colitis, diarrhoea, and fatigue in three (2%) patients each, and those attributed to chemotherapy were decreased neutrophil count (in 24 [17%] patients), neutropenia (22 [15%]), diarrhoea (14 [10%]), and fatigue (13 [9%]). Serious adverse events attributed to study treatment occurred in 25 (16%) patients in the pembrolizumab group and in 41 (29%) patients in the chemotherapy group. No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy. INTERPRETATION: In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in overall survival between the two treatment groups. These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. FUNDING: MSD.

Assessment of Clinical Response Following Atezolizumab and Bevacizumab Treatment in Patients With Neuroendocrine Tumors: A Nonrandomized Clinical Trial.

Importance: Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing. Objective: To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs. Design, Setting, and Participants: This single-arm, open-label nonrandomized clinical study in patients with rare cancers included 40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs [pNETs] and 20 with extrapancreatic NETs [epNETs]) treated at a tertiary care referral cancer center between March 31, 2017, and February 19, 2019. Data were analyzed from June to September 2021. Interventions: Patients received intravenous bevacizumab and atezolizumab at standard doses every 3 weeks until progression, death, or withdrawal. Main Outcomes and Measures: The primary end point was objective radiographic response using Response Evaluation Criteria in Solid Tumors, version 1.1, with progression-free survival (PFS) as a key secondary end point. Results: Following treatment of the 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pNETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with epNETs (15%; 95% CI, 3.2%-37.9%). The PFS was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months in these cohorts, respectively. Conclusions and Relevance: In this nonrandomized clinical trial, findings suggest that clinical responses in patients with NET may follow treatment with the combination of bevacizumab and atezolizumab, with a PFS consistent with effective therapies. Trial Registration: ClinicalTrials.gov Identifier: NCT03074513.

Cost-effectiveness of pembrolizumab for the first-line treatment of patients with unresectable or metastatic MSI-H/dMMR colorectal cancer in the United States.

AIMS: Approximately, 4% of Stage IV colorectal cancers (CRC) are microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors. Patients with metastatic MSI-H/dMMR CRC receiving conventional therapies experience lower response rates and tend to have worse overall survival compared with patients with microsatellite stable (MSS)/proficient mismatch repair (pMMR) CRC. Pembrolizumab received FDA approval in 2020 for first-line treatment of Stage IV MSI-H/dMMR CRC based on significantly longer progression-free survival versus standard of care (SoC, 5-fluorouracil-based therapy with or without bevacizumab or cetuximab). This study evaluated the cost-effectiveness of pembrolizumab vs. SoC as per KEYNOTE-177 and other first-line treatments for MSI-H/dMMR CRC from a US healthcare system perspective. METHODS: A three-health-state partitioned-survival model was built using progression-free and overall survival data from KEYNOTE-177 and a network meta-analysis. Utilities were derived from KEYNOTE-177 EQ-5D-3L data. Drug acquisition, administration, AE, surgery, monitoring, subsequent treatment, and terminal care costs were included. Sensitivity and scenario analyses were performed, including utilizing a state-transition model structure and adopting a societal perspective. RESULTS: Over a lifetime time horizon, pembrolizumab and SoC were associated with total QALYs of 4.85 and 3.23, and total costs of $381,735 and $370,465, respectively, resulting in an ICER of $6,984 per QALY. QALY gains were mainly driven by extended survival with pembrolizumab. Pembrolizumab incurred higher drug acquisition costs relative to SoC but was cost-saving in terms of drug administration, AE, monitoring, subsequent treatment, and terminal care. Pembrolizumab dominated FOLFOX + panitumumab, FOLFOXIRI, and FOLFOXIRI + bevacizumab, and presented ICERs of $35,220 and $276 against XELOX and XELOX + bevacizumab. Results were robust to sensitivity and scenario analyses. CONCLUSION: Pembrolizumab is highly cost-effective for the first-line treatment of unresectable or metastatic MSI-H/dMMR CRC in the US at a willingness-to-pay threshold of $100,000/QALY.Key messagesPembrolizumab is a highly cost-effective option for the first-line treatment of patients with unresectable or metastatic MSI-H/dMMR colorectal cancer in the United States at a willingness-to-pay threshold of $100,000. Compared with the current standard of care for these patients, pembrolizumab:Increases survival due to delaying and preventing progression;Increases QALYs due to longer survival, improvement in HRQoL in the progression-free health state, and fewer Grade 3+ adverse events;Reduces costs associated with administering treatment, managing adverse events, monitoring post-progression disease, providing subsequent treatment, and providing terminal care; andReduces indirect health care costs when taking a societal perspective due to productivity gains from delaying and preventing progression and death, less frequent treatment administration and less frequent Grade 3+ adverse events.

Comprehensive Clinical and Molecular Characterization of KRAS G12C-Mutant Colorectal Cancer.

PURPOSE: KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS: We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS: Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION: PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.

Antibiotic use influences outcomes in advanced pancreatic adenocarcinoma patients.

Recent studies defined a potentially important role of the microbiome in modulating pancreatic ductal adenocarcinoma (PDAC) and responses to therapies. We hypothesized that antibiotic usage may predict outcomes in patients with PDAC. We retrospectively analyzed clinical data of patients with resectable or metastatic PDAC seen at MD Anderson Cancer from 2003 to 2017. Demographic, chemotherapy regimen and antibiotic use, duration, type, and reason for indication were recorded. A total of 580 patients with PDAC were studied, 342 resected and 238 metastatic patients, selected retrospectively from our database. Antibiotic use, for longer than 48 hrs, was detected in 209 resected patients (61%) and 195 metastatic ones (62%). On resectable patients, we did not find differences in overall survival (OS) or progression-free survival (PFS), based on antibiotic intake. However, in the metastatic cohort, antibiotic consumption was associated with a significantly longer OS (13.3 months vs. 9.0 months, HR 0.48, 95% CI 0.34-0.7, p = 0.0001) and PFS (4.4 months vs. 2 months, HR 0.48, 95% CI 0.34-0.68, p = <0.0001). In multivariate analysis, the impact of ATB remained significant for PFS (HR 0.59, p = 0.005) and borderline statistically significant for OS (HR 0.69, p = 0.06). When we analyzed by chemotherapy regimen, we found that patients who received gemcitabine-based chemotherapy as first-line therapy (n = 118) had significantly prolonged OS (HR 0.4, p 0.0013) and PFS (HR 0.55, p 0.02) if they received antibiotics, while those receiving 5FU-based chemotherapy (n = 98) had only prolonged PFS (HR 0.54, p = 0.03). Antibiotics-associated modulation of the microbiome is associated with better outcomes in patients with metastatic PDAC.

Olaparib Monotherapy for Previously Treated Pancreatic Cancer With DNA Damage Repair Genetic Alterations Other Than Germline BRCA Variants: Findings From 2 Phase 2 Nonrandomized Clinical Trials.

IMPORTANCE: The subtype of pancreatic ductal adenocarcinoma cancer (PDAC) with DNA damage repair (DDR) deficiency from BRCA1/2 variants has a favorable prognosis and is sensitive to platinum analogues and poly-(adenosine diphosphate-ripose) polymerase (PARP) inhibition with olaparib. Approximately 10% to 20% of patients with PDAC have DDR genetic alterations other than germline BRCA variants. This population has been termed as having BRCAness. An opportunity exists to define the clinical phenotype, molecular underpinnings, and effectiveness of PARP inhibitors for this population. OBJECTIVE: To examine the therapeutic effectiveness of the PARP inhibitor olaparib for patients with pancreatic cancer with BRCAness. DESIGN, SETTING, AND PARTICIPANTS: Two parallel phase 2 nonrandomized clinical trials were conducted from November 11, 2016, to October 2, 2018, among 46 patients in Israel and Texas to determine the effectiveness of olaparib as monotherapy in advanced, previously treated PDAC with BRCAness. Inclusion criteria were treatment with 1 or more prior systemic therapies for advanced PDAC, Eastern Cooperative Oncology Group performance status of 0 to 1, and lack of the germline BRCA1/2 variant. BRCAness in these studies was defined as previously known DDR genetic alterations (DDR-GAs), personal or family history of BRCA-associated cancers (without DDR-GAs), or ATM protein loss as determined by immunohistochemistry. MAIN OUTCOMES AND MEASURES: The primary study end point was the objective response rate, and the secondary end points were progression-free survival and overall survival (OS). RESULTS: Forty-eight patients were enrolled, and 46 (26 women [57%]; mean [SD] age, 65.5 [11.1] years) were evaluable. The median treatment duration with olaparib was 3.0 months (interquartile range, 1.8-6.4 months). A total of 24 patients had the DDR phenotype (DDR-GAs), 17 had a family history of BRCA-associated cancers without DDR-GAs, and 5 had ATM loss as determined by immunohistochemistry. The DDR-GAs included ATM (n = 14), PALB2 (n = 2), ARID1A (n = 3), BRCA somatic (n = 1), PTEN (n = 1), RAD51 (n = 1), CCNE (n = 1), and FANCB (n = 2). Common toxic effects were grade 1 to 2 anemia, fatigue, anorexia, and nausea. One patient had a confirmed partial response (2%), 33 patients experienced stable disease (72%), of whom 11 (24%) experienced disease stability longer than 4 months and 12 patients had progressive disease (26%). The response duration for the patient with confirmed partial response was 3.9 months. Median progression-free survival was 3.7 months (95% CI, 2.9-5.7) and was significantly higher for patients with DDR-GAs (5.7 months; 95% CI, 3.6-8.8 months; P = .008) and platinum-sensitive PDAC (4.1 months; 95% CI, 3.6-7.8 months; P = .01). The estimated median OS was 9.9 months (95% CI, 7.6-16.1 months) in the study and 13.6 months (95% CI, 9.69 to not reached) in the prespecified DDR-GA cohort. CONCLUSIONS AND RELEVANCE: The definition of the BRCAness phenotype in PDAC may be limited to patients harboring DDR-GAs. In these 2 phase 2 nonrandomized clinical trials, olaparib was well tolerated and showed limited antitumor activity in patients with advanced, platinum-sensitive PDAC with DDR-GAs. These conclusions suggest a potential therapeutic opportunity for a subset of patients with PDAC.

Radiographic and Serologic Predictors of Pathologic Major Response to Preoperative Therapy for Pancreatic Cancer.

OBJECTIVE: We sought to identify potential radiologic and serologic markers of pancreatic tumor response to therapy, using pathologic major response (pMR) as the objective endpoint. BACKGROUND: We previously demonstrated that a pMR to preoperative therapy, defined as detection of <5% viable cancer cells in the surgical specimen on histopathological analysis, is an important prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Pretreatment and posttreatment computed tomography scans of consecutive patients who received preoperative chemotherapy and/or (chemo)radiation before pancreatectomy for PDAC between January 2010 and December 2018 were rereviewed. Response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, other radiographic changes in tumor size and anatomic extent, and posttreatment CA 19-9 levels were compared between patients who did and did not have a pMR on final histopathologic analysis of their surgical specimens. RESULTS: A total of 290 patients with localized PDAC underwent pancreatectomy between 2010 and 2018 after receiving preoperative chemotherapy (n = 36; 12%), (chemo)radiation (n = 87; 30%), or both (n = 167; 58%). Among them, 28 (10%) experienced pMR, including 9 (3.1%) who experienced pathologic complete response. On multivariable logistic regression, low posttreatment CA 19-9 level, RECIST partial response, and reduction in tumor volume were confirmed to be independently associated with pMR (P < 0.01). CONCLUSIONS: We identified serologic and radiographic indicators of pMR that could help inform the delivery of preoperative therapy to patients with PDAC.

Trial Sponsorship and Time to Reporting for Phase 3 Randomized Cancer Clinical Trials.

The pace of clinical trial data generation and publication is an area of interest within clinical oncology; however, little is known about the dynamics and covariates of time to reporting (TTR) of trial results. To assess these, ClinicalTrials.gov was queried for phase three clinical trials for patients with metastatic solid tumors, and the factors associated with TTR from enrollment completion to publication were analyzed. Based on the 319 included trials, cooperative-group-sponsored trials were reported at a slower rate than non-cooperative-group trials (median 37.5 vs. 31.0 months; p < 0.001), while industry-funded studies were reported at a faster rate than non-industry-supported trials (31.0 vs. 40.0 months; p = 0.005). Furthermore, successful trials (those meeting their primary endpoint) were reported at a faster rate than unsuccessful studies (27.5 vs. 36.0 months; p < 0.001). Multivariable analysis confirmed that industry funding was independently associated with a shorter TTR (p = 0.006), while cooperative group sponsorship was not associated with a statistically significant difference in TTR (p = 0.18). These data underscore an opportunity to improve cooperative group trial efficiency by reducing TTR.

FOLFOXIRI Versus Doublet Regimens in Right-Sided Metastatic Colorectal Cancer: Focus on Subsequent Therapies and Impact on Overall Survival.

INTRODUCTION: It has been determined that right-sided metastatic colorectal cancer (mCRC) has a worse prognosis for overall survival (OS). Currently, there is no consensus on the best systemic regimen for treatment-naive right-sided tumors. We compared the impact of subsequent therapies on OS of patients treated with FOLFOXIRI (leucovorin, 5-fluorouracil, oxaliplatin, irinotecan) versus doublet regimens. PATIENTS AND METHODS: Data of patients with treatment-naive right-sided mCRC who received FOLFOXIRI or doublet regimens between January 2001 to December 2018 were retrospectively analyzed. OS was compared between the two groups, and prognostic factors were assessed by multivariate analysis. RESULTS: A total of 196 patients were selected; 33 patients received FOLFOXIRI and 163 patients doublet therapy. Median follow-up was 82.3 months. The FOLFOXIRI cohort received fewer subsequent lines of therapies (61% vs. 78%, P = .043). The greater the number of subsequent lines of therapy, the lower the risk of death (hazard ratio [95% confidence interval] 0.67 [0.46-0.99], 0.62 [0.45-0.86], and 0.56 [0.39-0.81] for > 1, > 2, and > 3 lines, respectively). By multivariate analysis, metastasectomy and bevacizumab with subsequent lines of therapy were the variables with greatest positive impact on OS (respectively, hazard ratio [95% confidence interval] 0.54 [0.38-0.78] and 0.61 [0.44-0.84]). CONCLUSION: Patients with treatment-naive right-sided mCRC who received front-line FOLFOXIRI had a lower number of subsequent therapies than patients who received doublet regimens. Our findings highlight the relevance of the continuum of care in mCRC, regardless of the first-line regimen, and the importance of careful selection of patients for the FOLFOXIRI regimen.

Response and Survival Associated With First-line FOLFIRINOX vs Gemcitabine and nab-Paclitaxel Chemotherapy for Localized Pancreatic Ductal Adenocarcinoma.

Importance: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel (GA) are first-line chemotherapy regimens for pancreatic cancer. Their relative efficacy in the setting of localized disease is unknown. Objective: To evaluate radiographic and serologic measures of responses associated with first-line chemotherapy with FOLFIRINOX or GA, and to determine the association between these drug regimens, putative measures of response, and survival. Design, Setting, and Participants: This case series assessed 485 consecutive patients who were diagnosed as having previously untreated localized pancreatic ductal adenocarcinoma at The University of Texas MD Anderson Cancer Center between January 1, 2010, and December 31, 2017, and who received at least 3 cycles of first-line chemotherapy with FOLFIRINOX or GA. The median (range) follow-up duration was 33 (2-28) months. Exposures: Administration of FOLFIRINOX (285 patients [59%]) or GA (200 patients [41%]) as first-line chemotherapy. Main Outcomes and Measures: Resection rate, radiographic metrics (Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, and change in tumor volume or anatomic staging), a serologic metric (serum cancer antigen 19-9 level), and overall survival after administration of first-line chemotherapy. Results: In total, 485 patients (266 [55%] male) were included in the analysis. Patients treated with FOLFIRINOX were generally younger (median [range] age at diagnosis: 61 [30-81] vs 71 [36-89] years; P = .001) and had better performance status as indicated by the Eastern Cooperative Oncology Group scale (range 0-4, with lower numbers representing better performance) score of 2 or lower (274 patients [96%] vs 165 patients [82%] P = .001) but more invasive tumors than patients who received GA (91 [32%] vs 90 [45%] resectable tumors; P = .01). After propensity score matching to control for these biases, many objective serologic and radiographic metrics of response associated with administration of FOLFIRINOX or GA-including low rates of local tumor downstaging-did not differ. However, RECIST partial response was more common among patients treated with FOLFIRINOX (27 of 140 patients [19%]) than with GA (8 of 140 patients [6%]; P = .001). Moreover, (chemo)radiation (50% vs 34%; P = .001) was more commonly administered to and pancreatectomy (27% vs 16%; P = .01) was subsequently performed more frequently for patients initially treated with FOLFIRINOX. The overall survival duration of patients treated with either regimen was similar (hazard ratio, 1.48; 95% CI, 0.97-2.26; P = .07). Conclusions and Relevance: In this cohort of patients with localized pancreatic adenocarcinoma who received FOLFIRINOX or GA as their first line of therapy, FOLFIRINOX was associated with higher rates of RECIST partial response and subsequent pancreatectomy than GA, but the overall survival associated with these regimens was similar.

Bevacizumab Does Not Influence the Efficacy of Partial Splenic Embolization in the Management of Chemotherapy-Induced Hypersplenism.

BACKGROUND: Antiangiogenics attenuate chemotherapy-related hepatotoxicity and portal hypertension. The potential impact of bevacizumab on the efficacy and safety of partial splenic embolization (PSE) in the management of chemotherapy-induced hypersplenism (CIH) has never been investigated. PATIENTS AND METHODS: We conducted a retrospective study with gastrointestinal cancer patients who have undergone PSE for the treatment of thrombocytopenia resulting from hypersplenism. Pre- and post-PSE platelet count (PC), the percentage of patients who resumed systemic therapy, and complication rates were compared between patients exposed and not exposed to bevacizumab. RESULTS: A total of 110 patients were eligible. Colorectal cancer was the predominant neoplasm (60%), and 5-fluorouracil, oxaliplatin, and bevacizumab were the most commonly provided drugs (70%, 65%, and 65% of patients, respectively). After PSE, 80% of patients recovered PC ≥ 100 × 109/L (100K). Systemic therapy was resumed in 81% of patients. Seventy-one patients exposed to bevacizumab had a median PC before PSE of 77.5K and after PSE of 167.0K, with a mean difference of 108K (P < .0001). Thirty-nine patients not exposed to bevacizumab had a median PC of pre-PSE of 73.0K and post-PSE of 187.0K, with a mean difference of 117.7K (P < .0001). Both groups had similar values of percentages of patients with PC post-PSE ≥ 100K (83% vs. 74%; P = .463), resumption of systemic therapy (85% vs. 74%; P = .213), and complication rates. A linear association between splenic infarction rate and increment in PC was found (P < .0001). CONCLUSION: PSE is a safe and effective procedure in the management of CIH, regardless of the provision of bevacizumab. Splenic infarction rate should be optimized to enhance patient outcomes.

Modified gemcitabine plus nab-paclitaxel regimen in advanced pancreatic ductal adenocarcinoma.

BACKGROUND: Gemcitabine (GEM) plus nab-paclitaxel (NabP) (GEM 1000 mg/m2 IV over 30 minutes + NabP 125 mg/m2 IV given days 1, 8, and 15 every 28 days) is one of the two standard of care combination therapies for metastatic pancreatic ductal adenocarcinoma (PDAC). Our cancer center has utilized GEM-NabP given every two-weeks due to tolerability and patient convenience. Here, we review the safety and efficacy of this modified regimen. METHODS: Metastatic PDAC patients (pts) who initiated front-line or second-line GEM-NabP during 2013-2017 were retrospectively reviewed. Primary objective was overall survival. Secondary objectives were disease control rate, progression-free survival, and the incidence of dose delays and/or adjustments. RESULTS: From a total of 235 patients, 140 pts received GEM-NabP front-line while 95 pts received GEM-NabP second-line. Median dosing was 600 mg/m2 at fixed-dose rate for GEM and 125 mg/m2 for NabP given predominantly (~90%) every two-weeks. Eastern Cooperative Group performance status of 0 and 1 pts had front-line OS of 12.7 and 9.6 months and when given second-line had OS of 8 months and 7.3 months, respectively. ECOG 0 and 1 pts had front-line progression-free survival (PFS) of 5.3 months and 2.8 months and second-line PFS was 3.5 months and 2.4 months, respectively. Treatment was well tolerated with limited dose modifications. CONCLUSION: Our analysis revealed safety with every two-week low dose GEM-NabP while maintaining efficacy. Patient schedule convenience should factor into metastatic incurable malignancies. We suggest the use of every two-week GEM-NabP particularly in patients desiring a modified schedule.

Phase I study of DFP-11207, a novel oral fluoropyrimidine with reasonable AUC and low Cmax and improved tolerability, in patients with solid tumors.

5-fluorouracil (5-FU) and 5-FU derivatives, such as capecitabine, UFT, and S-1, are the mainstay of chemotherapy treatment for gastrointestinal cancers, and other solid tumors. Compared with other cytotoxic chemotherapies, these drugs generally have a favorable safety profile, but hematologic and gastrointestinal toxicities remain common. DFP-11207 is a novel oral cytotoxic agent that combines a 5-FU pro-drug with a reversible DPD inhibitor and a potent inhibitor of OPRT, resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicities. In this Phase I study (NCT02171221), DFP-11207 was administered orally daily, in doses escalating from 40 mg/m2/day to 400 mg/m2/day in patients with esophageal, colorectal, gastric, pancreatic or gallbladder cancer (n = 23). It was determined that DFP-11207 at the dose of 330 mg/m2/day administered every 12 hours was well-tolerated with mild myelosuppressive and gastrointestinal toxicities. The pharmacokinetic analysis determined that the 5-FU levels were in the therapeutic range at this dose. In addition, fasted or fed states had no influence on the 5-FU levels (patients serving as their own controls). Among 21 efficacy evaluable patients, 7 patients had stable disease (33.3%), of which two had prolonged stable disease of >6 months duration. DFP-11207 can be explored as monotherapy or easily substitute 5-FU, capecitabine, or S-1 in combination regimens.

The Sequential Radiographic Effects of Preoperative Chemotherapy and (Chemo)Radiation on Tumor Anatomy in Patients with Localized Pancreatic Cancer.

BACKGROUND: The incidence and magnitude of indicators of radiographic response of pancreatic cancer to systemic chemotherapy and (chemo)radiation administered prior to anticipated pancreatectomy are unclear. METHODS: Sequential computed tomography scans of 226 patients with localized pancreatic cancer who received chemotherapy consisting of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) or gemcitabine and nanoparticle albumin-bound paclitaxel (GA) with or without (chemo)radiation and who subsequently underwent surgery with curative intent from January 2010 to December 2018 at The University of Texas MD Anderson Cancer Center and Verona University Hospital were re-reviewed and compared. RESULTS: Overall, 141 patients (62%) received FOLFIRINOX, 70 (31%) received GA, and 15 (7%) received both; 164 patients (73%) received preoperative (chemo)radiation following chemotherapy and prior to surgery; and 151 (67%), 70 (31%), and 5 (2%) patients had Response Evaluation Criteria in Solid Tumors (RECIST) stable disease, partial response, and progressive disease, respectively. The tumors of 29% of patients with borderline resectable or locally advanced cancer were downstaged after preoperative therapy. Radiographic downstaging was more common with chemotherapy than with (chemo)radiation (24% vs. 6%; p = 0.04), and the median tumor volume loss after chemotherapy was significantly greater than that after (chemo)radiation (28% vs. 17%; p < 0.01). CONCLUSIONS: Less than one-third of patients treated with FOLFIRINOX or GA with or without (chemo)radiation experienced either RECIST partial response or radiographic downstaging prior to surgery. The incidence of tumor downstaging was higher and the magnitude of tumor volume loss was greater following chemotherapy than after (chemo)radiation.

A Randomized, Placebo-Controlled, Double-Blind Study of Minocycline for Reducing the Symptom Burden Experienced by Patients With Advanced Pancreatic Cancer.

CONTEXT: Although it is well known that patients with advanced pancreatic cancer (PC) experience significant symptom burden, few strategies for effective symptom intervention are available for them. OBJECTIVES: To investigate the efficacy of minocycline, an anti-inflammatory agent, for symptom reduction in patients with advanced PC. METHODS: We conducted Phase II, randomized, and placebo-controlled trial to obtain preliminary estimates of the effects on symptom reduction with 100 mg of minocycline or placebo given twice a day. Eligible patients had diagnosed advanced PC and were scheduled for standard chemotherapy. Patient-reported symptoms were measured weekly during the eight-week trial using the MD Anderson Symptom Inventory (MDASI) module in patients with gastrointestinal cancer. The primary outcome measure was the area under the curve values of the five most severe symptoms in the two arms. RESULTS: Of the 44 patients recruited, 31 (71%) were evaluable for the primary efficacy analysis, with 18 received minocycline and 13 placebo. Fatigue, pain, disturbed sleep, lack of appetite, and drowsiness were the most severe symptoms reported by both groups. No significant differences in area under the curve values over time between the study arms were found for the composite MDASI score or single-item scores of the five most severe MDASI items. No treatment-related deaths were reported, and no Grade 3-4 toxicities were observed. CONCLUSION: Minocycline is safe for use in patients receiving treatment for PC. There is no observed symptom reduction with minocycline on the major symptom burden associated with advanced PC compared with placebo. Attrition because of rapid disease progression impacted the study significantly.

Modified FOLFIRINOX in pancreatic cancer patients Age 75 or older.

BACKGROUND: Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population. METHODS: We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011 to 2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT). RESULTS: 24 pts were included. Grade 3 or 4 HT occurred in 11 pts 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Median PFS was 3.7 months (95% CI: 3.0-5.7) with a median OS of 11.6 months (95% CI: 6.14-15.7). For first line pts, median PFS and OS were 5.1 (95% CI: 2.0-12.8) and 12.2 months (95% CI: 4.8-30.8), respectively. CONCLUSIONS: In this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts.