Carmen Joseph Allegra

Improvements in cancer treatment are guided by randomized clinical trials (RCTs) that reliably assess the therapeutic impact of adding experimental treatments into clinical practice. The fundamental value of RCTs is that the difference in outcomes between the experimental and control arms provides an unbiased estimate of the risk-benefit ratio for the experimental treatment. However, the clinical relevance of trial results depends on the control arm accurately reflecting the appropriate standard of care (SOC) in the intended-use population. Due to the accelerating pace of cancer treatment development, it is becoming more common for the SOC to change during an ongoing randomized trial. This increasingly dynamic SOC landscape may have a nontrivial impact on the conduct and interpretation of future RCTs, and thus it is important to appreciate these issues and, when possible, prospectively address them when designing and conducting clinical trials. We review common scenarios where the SOC changes and provide recommendations on how to design a trial to minimize the impact of such changes when the trial is ongoing.

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.

An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal–Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the United States. Although immunotherapy has dramatically changed the landscape of treatment for many advanced cancers, the benefit in CRC has thus far been limited to patients with microsatellite instability high (MSI-H):DNA mismatch repair–deficient (dMMR) tumors. Recent studies in the refractory CRC setting have led to US Food and Drug Administration approvals for pembrolizumab as well as nivolumab (with or without ipilimumab) for tumors harboring an MSI-H:dMMR molecular profile. Several randomized controlled trials are underway to move immunotherapy into the frontline for metastatic cancer (with or without chemotherapy) and the adjuvant setting. Awareness of these studies is critical given the relatively low incidence (approximately 3%–5%) of MSI-H:dMMR in advanced or metastatic CRC to support study completion, because the results could be potentially practice changing. The real challenge in this disease is related to demonstrating the benefit of immunotherapy for the vast majority of patients with CRC not harboring MSI-H:dMMR. Given the rapid pace of scientific changes, this article provides a narrative review regarding the current landscape of immunotherapy for CRC. Particular attention is paid to the currently available data that inform today’s clinical practice along with upcoming randomized controlled trials that may soon dramatically change the treatment landscape for CRC.

3603 Background: Sex is one of several factors known to affect drug efficacy and toxicity. Preliminary data in different types of cancers suggest a higher toxicity of chemotherapy in women. Aim of this pooled analysis was to understand the clinical relevance of sex differences in toxicity of ACT in CC. Methods: The primary aim was to compare these major AEs: nausea, vomiting, stomatitis, diarrhea, leucopenia, neutropenia, anemia, thrombocytopenia, and neuropathy (pts receiving oxaliplatin) between men (M) and women (W) treated with ACT after curative resection. Severity of AEs was categorized as per NCI criteria. Comparisons were conducted by chi-squared test and logistic regression based on type of ACT, including fluoropyrimidine (5-FU) as single-agent, 5-FU + irinotecan (FOLFIRI), or 5-FU + oxaliplatin (FOLFOX). P < 0.001 was considered significant due to multiple comparisons. Results: AE data were available in 28,636 pts (54% M) from 26 studies. Overall, women were at greater risk for the majority of toxicities (see Table). Conclusions: Further investigations are needed to better understand the impact of sex on toxicity and efficacy of chemotherapy. Possible differences in perception do not explain the significant differences in neutropenia. These results suggest that sex-specific strategies for drug dosing and supportive care may need consideration.

3514 Background: The predictive value of tumor sidedness in colorectal cancer is currently of interest especially in metastatic setting for anti-EGFR therapy response. We tested whether intrinsic molecular subtype classification predictive of treatment benefit in stage II/III colon cancer is an independent novel marker in association with tumor sidedness. Methods: All available cases included in the NSABP/NRG C-07 trial for which we had both gene expression data and anatomical data (n=1603) were used to determine the molecular subtypes using the following classifiers; the Colorectal Cancer Assigner (CRCA), the Colon Cancer Subtypes (CCS) and the Consensus Molecular Subtypes (CMS). Frequency of tumor sidedness in each subtype and recurrence-free survival were analyzed. Results: Intrinsic subtypes were differentially distributed in right- and left-colon tumors with the exception of the stem-like or CMS4 (mesenchymal) subtype (Table 1). Sidedness was not associated with prognosis (p=0.82, HR: 1.022 [CI: 0.851-1.227]) or prediction of patients with greater benefit from oxaliplatin when combined with 5-Fu+LV (interaction p=0.484). Conclusions: Although tumor sidedness is associated with distribution of intrinsic subtypes in stage II/III colon cancer, it is not predictive of survival benefit from oxaliplatin in C-07. Support: -180868, -180822, U24-CA196067; HI13C2162; PA DOH; Sanofi-Synthelabo Clinical trial information: NCT00004931.

3510Background: In the C-07 trial for stage II/III colon cancer, oxaliplatin added to 5-fluorouracil + leucovorin (FULV) provided significant but modest absolute benefit for DFS. We hypothesized that molecular subtypes would be associated with differential prognosis and benefit from oxaliplatin. Methods: C-07 cases were divided into discovery (n = 848) and validation (n = 881) cohorts based on the chronological order of tissue block submission. Patients (pts) from a discovery cohort were subtyped with the CRCA classifier described by Sadanandam et al (enterocyte, goblet-like, transit amplifying, stem-like, and inflammatory). A re-estimated centroid using 72 genes included in a custom nCounter gene code set was used to determine subtypes and their association with oxaliplatin benefit in the discovery cohort. The validation cohort was then prospectively examined with a prespecified statistical analysis plan. Post-hoc analysis included examination of the entire cohort with CRCA, CCS and CMS subtyping methods...

TPS190 Background: Resection of colorectal cancer hepatic metastases can provide long-term survival for 20-40% of patients (pts) without extrahepatic disease who undergo complete ("curative") surgical resection of liver tumors. Cytotoxic chemotherapy given to patients with liver-only metastatic colorectal cancer has been shown to convert some pts whose liver tumors were considered unresectable to resectable with improvement in long-term survival for pts undergoing potentially curative resection (Pozzo et al. Ann Oncol 15:933.2004). KRAS status has been shown to predict for benefit from EGFR inhibitors. Escalation of cetuximab (EVEREST trial) demonstrated that tumor response rates can be enhanced from 13% to 30% with escalation of cetuximab dose (Tejpar et al JCO 25(18s) abst 4037, 2007). The primary goal of neoadjuvant chemotherapy with targeted therapy for unresectable, liver-only metastatic colorectal cancer is to produce enough tumor shrinkage to allow a curative metastasectomy. A secondary goal of che...

Dihydropteroate synthase is the target enzyme for the sulfonamide compounds, which are the mainstay of therapy for Pneumocystis carinii pneumonia, a common infection in patients with impaired immunity. The stability of this enzyme, its kinetic constants with respect to substrates, and the 50% inhibitory concentration (IC₅₀) of several sulfonamides and the sulfone dapsone have been characterized using both cell-free and intact organism assay systems. Stability of the enzyme is dependent on storage temperature, reducing reagents, and to a lesser extent, protease inhibitors. The sulfonamides sulfadiazine and sulfamethoxazole were found to be highly potent inhibitors of P. carinii dihydropteroate synthase with IC₅₀s of 0.42 and 0.71 μM, respectively. Dapsone had equivalent potency when compared with the most potent sulfonamides tested in both assay systems. Data suggest that sulfamethoxazole, sulfadiazine, and dapsone may represent equivalent choices as P. carinii dihydropteroate synthase inhibitors, assuming an equivalent in vivo drug exposure can be achieved.