PracticeUpdate: Haematology & Oncology

COLON & RECTUM

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Primary tumour location predicts response to therapy for RAS wt Comment by Axel Grothey MD

JOURNAL SCAN Association of proton pump inhibitors and capecitabine efficacy in advanced gastroesophageal cancer: secondary analysis of the TRIO-013/LOGiC randomized clinical trial JAMA Oncology Take-home message • This was a secondary analysis of a previous randomized, phase III trial comparing capecitabine and oxaliplatin (CapeOx) with or without lapatinib in 545 patients with HER2- positive metastatic gastroesophageal cancer (GEC). The current report examines whether concurrent proton pump inhibitor (PPI) therapy had a negative effect on progression-free and overall survival rates. Of the 545 patients enrolled on this trial, 229 (42.0%) received PPIs. In multivariate analysis, patients who received PPIs with chemotherapy had nearly 40%worse overall survival compared with those not receiving PPIs. • PPIs decrease the efficacy of capecitabine on overall survival, a finding consistent with earlier reports on PPIs with erlotinib and sunitinib. Studies to determine the impact of PPIs on outcome when lapatinib is combined with capecitabine are ongoing. Abstract IMPORTANCE Capecitabine is an oral cytotoxic chemotherapeutic commonly used across cancer subtypes. As with other oral medications though, it may suffer from drug interactions that could impair its absorption. OBJECTIVE To determine if gastric acid suppressants such as proton pump inhibitors (PPIs) may impair capecitabine efficacy. DESIGN, SETTING, AND PARTICIPANTS This secondary analysis of TRIO-013, a phase III randomized trial, compares capecitabine and oxaliplatin (CapeOx) with or without lapatinib in 545 patients with ERBB2/HER2- positive metastatic gastroesophageal cancer (GEC); patients were randomized 1:1 between CapeOx with or without lapatinib. Proton pump inhibitor use was identified by medication records. Progression-free survival (PFS) and overall survival (OS) were compared between patients treated with PPIs vs patients who were not. Specific subgroups were accounted for, such as younger age (<60 years), Asian ethnicity, female sex, and disease stage (metastatic/advanced) in multivariate Cox proportional hazards modeling. The TRIO-013 trial accrued and randomized patients between June 2008 and January 2012; this analysis took place in January 2014. INTERVENTIONS Patients were divided based on PPI exposure. MAIN OUTCOMES AND MEASURES Primary study out- come was PFS and OS between patients treated with PPIs vs patients who were not. Secondary outcomes included disease response rates and toxicities. RESULTS Of the 545 patients with GEC (median age, 60 years; 406 men [74%]) included in the study, 229 received PPIs (42.0%) and were evenly distributed between arms. In the placebo arm, PPI- treated patients had poorer median PFS, 4.2 vs 5.7 months (hazard ratio [HR], 1.55; 95% CI, 1.29–1.81, P<0.001); OS, 9.2 vs 11.3 months (HR, 1.34; 95% CI, 1.06–1.62; P=0.04); and disease control rate (83% vs 72%; P=0.02) vs patients not treated with PPIs. In multivariate analysis considering age, race, disease stage, and sex, PPI-treated patients had poorer PFS (HR, 1.68; 95% CI, 1.42–1.94; P<0.001) and OS (HR, 1.41; 95% CI, 1.11–1.71; P=0.001). In patients treated with CapeOx and lapatinib, PPIs had less effect on PFS (HR, 1.08; P=0.54) and OS (HR, 1.26; P=0.10); however, multivariate analysis in this group demonstrated a significant difference in OS (HR, 1.38; 95% CI, 1.06–1.66; P=0.03). CONCLUSIONS AND RELEVANCE Proton pump inhibitors negatively effected capecitabine efficacy by possi- bly raising gastric pH levels, leading to altered disso- lution and absorption. These results are consistent with previous erlotinib and sunitinib studies. Whether PPIs affected lapatinib is unclear given concurrent capecitabine. Given capecitabine’s prevalence in treatment breast cancer and colon cancer, further studies are under way. Association of proton pump inhibitors and capecitabine efficacy in advanced gastroe- sophageal cancer: secondary analysis of the TRIO-013/LOGiC randomized clinical trial. JAMA Oncol 2016 Oct 13;[Epub ahead of print], Chu MP, Hecht JR, Slamon D, et al.

T he prognostic implication of sided- ness had long been known, but has routinely been ignored. With the emergence of routine molecular profiling and gene expression studies, differences in pathway alteration and genetic markers between right- and left-sided cancers have been identified. Consistently, all results presented so far, whether derived from the SEER population database or clinical trials, demonstrate that right-sided cancers (cecum to splenic flexure) are associated with worse prognosis. In addition to the currently published data from the CRYSTAL and FIRE-3 trials, the most intriguing findings with potential immediate treatment implications came from an analysis of the large phase 3 trial 80405, which compared chemotherapy plus cetuximab or bevacizumab in KRAS wild- type CRC. The prognostic implication of sidedness was confirmed with a difference of about 14 months in favor of left-sided cancers when all treatment arms were combined.

Importantly, though, the difference in overall survival for sidedness in patients treated with bevacizumab was much smaller compared with the difference observed with cetuximab (7 vs 19 months; BEV R vs L, 24.2 vs 31.4 months; CET R vs L, 16.7 vs 36.0 months). These results, which are very consistent with data presented from the FIRE-3 trial about 2 years ago, raise important questions for clinical practice: Should EGFR mAbs ever be considered for right-sided cancers at all? If the answer is “no,” would this only be applicable to first-line therapy or include later lines, too? On the other hand, should EGFR mAbs be considered the biologics of choice for first-line therapy of left-sided cancers? In addition, what are the biologic reasons for the apparent poorer outcome and the lack of (or at least lower) activity of EGFR mAbs in right- sided colon cancers? It has long been known that right-sided cancers are characterised by a higher rate of BRAF V600E mutations, more frequent MSI-H status, older age, and female gender. A single-institution study explored additional molecular features like CIMP (methylation status), RAS mutations, and EGFR ligand expression levels, and found that, when all these factors were put into a multivariate analysis, sidedness was no longer statistically significant for overall survival. The retrospective, nonrandomised data could provide us a way forward to find a molecular explanation for the observed out- comes results, perhaps with added information from microbiome studies. Having said that, the simplicity of sidedness as a prognostic and conceivably predictive marker in addition to RAS, BRAFmutation, andMSI testing makes it an attractive and readily available parameter to help guide clinical decision-making.

Some of the most important results presented at ASCO 2016 in colorectal cancer (CRC) were the consistent data on the prognostic and potentially predictive influence of sidedness on treatment outcomes.

Dr Grothey is Consultant, Division of Medical Oncology,

Department of Oncology, Mayo Clinic; Professor of Oncology, Clinical and Translational Science, Mayo Graduate School, Rochester, Minnesota.

Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials JAMA Oncology Take-home message

(n = 142 and n = 157, respectively) had markedly superior PFS, OS, and ORR compared with patients with right-sided tumors (n=33 and n=38, respectively). Among CRYSTAL and FIRE-3 study patients with RAS wt left-sided tumors, FOLFIRI plus cetuximab significantly improved OS relative to the respective comparators (FOLFIRI and FOLFIRI plus bevacizumab); in contrast, in RAS wt patients with poor-prognosis right-sided tumors, limited efficacy benefits were observed upon the addition of cetuximab to FOLFIRI in CRYSTAL, and comparable outcomes were observed between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab arms of FIRE-3. A significant interaction was observed between primary tumor location and treatment for OS (CRYSTAL: hazard ratio [HR], 1.95; 95% CI, 1.09–3.48 and FIRE-3: HR, 0.40; 95% CI, 0.23–0.70) within the RAS wt populations of both studies in multivariable models that also included sex, prior adjuvant therapy, and BRAF mutational status. CONCLUSIONS AND RELEVANCE In the RAS wt populations of CRYSTAL and FIRE-3, patients with left-sided tumors had a markedly better prognosis than those with right-sided tumors. First-line FOLFIRI plus cetuximab clearly benefitted patients with left-sided tumors (vs FOLFIRI or FOLFIRI plus bevacizumab, respectively), whereas patients with right-sided tumors derived limited benefit from standard treatments. JAMA Oncol 2016 Oct 10;[Epub ahead of print], Tejpar S, Stintzing S, Ciardiello F, et al.

• This retrospective study investigated the predictive value of primary tumor location in patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC). Tumor location was defined as left- or right-sided in patients enrolled in the CRYSTAL and FIRE-3 clinical trials. Objective response rate and progression-free and overall survival rates were better for the 299 patients with left-sided tumors than for the 71 patients with right-sided tumors. Patients with left-sided tumors also had an improved rate of overall survival following first-line therapy with FOLFIRI plus cetuximab vs FOLFIRI alone or FOLFIRI plus bevacizumab. • The prognosis for patients with left-sided RAS wt mCRC tumors was significantly better than for patients with right-sided tumors. Patients with right-sided tumors did not respond to the standard treatments, while patients with left-sided tumors responded well to treatment with FOLFIRI plus cetuximab. Abstract

DESIGN, SETTING, AND PARTICIPANTS In this retrospective analysis patients with RAS wt metastatic colorectal cancer from the CRYSTAL and FIRE-3 trials were classified as having left- sided or right-sided mCRC, defined, respectively, as patients whose tumors originated in the splenic flexure, descending colon, sigmoid colon, or rectum vs appendix, cecum, ascending colon, hepatic flexure, or transverse colon. MAIN OUTCOMES AND MEASURES Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were assessed according to tumor location and treatment arm. RESULTS In the RAS wt populations of the CRYSTAL and FIRE-3 trials, patients with left-sided tumors

IMPORTANCE Metastatic colorectal cancer (mCRC) is heterogeneous, and primary tumors arising from different regions of the colon are clinically and molecularly distinct. OBJECTIVE To examine the prognostic and predictive value of primary tumor location in patients with RAS wild-type (wt) mCRC treated with first-line fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab in the Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial and FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment For Patients With Metastatic Colorectal Cancer (FIRE-3) trial.

VOL. 1 • No. 5 • 2016