PURPOSE Consensus molecular subtypes (CMSs) were evaluated as prognostic and predictive biomarkers of patients with RAS wild-type metastatic colorectal cancer (mCRC) receiving fluorouracil and folinic acid (FU/FA) with or without panitumumab (Pmab) after Pmab + mFOLFOX6 induction within the randomized phase II PanaMa trial. METHODS CMSs were determined in the safety set (ie, patients that received induction) and full analysis set (FAS; ie, randomly assigned patients who received maintenance) and correlated with median progression-free survival (PFS) and overall survival (OS) since the start of induction or maintenance treatment and objective response rates (ORRs). Hazard ratios (HRs) and 95% CI were calculated by univariate/multivariate Cox regression analyses. RESULTS Of 377 patients of the safety set, 296 (78.5%) had available CMS data: CMS1/2/3/4: 29 (9.8%)/122 (41.2%)/33 (11.2%)/112 (37.8%) and unclassifiable: 17 (5.7%). The CMSs were prognostic biomarkers in terms of PFS ( P < .0001), OS ( P < .0001), and ORR ( P = .02) since the start of induction treatment. In FAS patients (n = 196), with CMS2/4 tumors, the addition of Pmab to FU/FA maintenance therapy was associated with longer PFS (CMS2: HR, 0.58 [95% CI, 0.36 to 0.95], P = .03; CMS4: HR, 0.63 [95% CI, 0.38 to 1.03], P = .07) and OS (CMS2: HR, 0.88 [95% CI, 0.52 to 1.52], P = .66; CMS4: HR, 0.54 [95% CI, 0.30 to 0.96], P = .04). The CMS interacted significantly with treatment in terms of PFS (CMS2 v CMS1/3: P = .02; CMS4 v CMS1/3: P = .03) and OS (CMS2 v CMS1/3: P = .03; CMS4 v CMS1/3: P < .001). CONCLUSION The CMS had a prognostic impact on PFS, OS, and ORR in RAS wild-type mCRC. In PanaMa, Pmab + FU/FA maintenance was associated with beneficial outcomes in CMS2/4, whereas no benefit was observed in CMS1/3 tumors.
3537 Background: Consensus molecular subtypes (CMS1-4) of colorectal cancer were evaluated as prognostic and predictive biomarkers in the PANAMA trial. PANAMA compared maintenance therapy with panitumumab (Pmab) and fluorouracil/folinic acid (FU/FA) vs. FU/FA alone after Pmab-FOLFOX induction therapy in RAS wildtype mCRC. Methods: Gene expression was measured after mRNA isolation in 179 of 248 patients of the full analysis set. The analysis was conducted using a customized Nanostring PanCancer Progression Panel. The original CMS classifier was re-derived for Nanostring data using a multinomial regression analysis.Median progression-free (PFS) and overall survival (OS) since start of maintenance were estimated by Kaplan-Meier-method and Cox-regression, using the log rank test. Objective response rates (ORR) of maintenance therapy were compared by Chi-square-test. Results: Prevalence of CMS was: CMS1, n = 15 (8.4 %); CMS2, n = 82 (45.8 %); CMS3, n = 20 (11.2 %) and CMS4, n = 62 (34.6 %). A prognostic impact of CMS regardless of treatment was not evident for PFS (p = 0.245) and OS (p = 0.169), but for ORR (p = 0.022), with CMS1 and CMS3 being associated with unfavourable efficacy during maintenance therapy. Potential predictive effects of CMS were observed in patients with CMS2 and CMS4 tumours. In CMS2 and CMS4 tumours, ORR was significantly higher when treated with Pmab-FU/FA in maintenance therapy (CMS2: 56.5% vs 30.6%, p = 0.026; CMS4: 55.6% vs. 28.6%, p = 0.040). In patients with CMS2 mCRC, this translated into a significant effect on PFS (Hazard ratio: 0.61 (95% CI 0.38 – 0.99) p = 0.046 (Table). Conclusions: CMS have limited prognostic impact for pmab-based maintenance therapy. However, CMS2 and CMS4 are positively associated with Pmab efficacy during maintenance therapy in the PANAMA trial. Further trials are necessary to confirm these results. [Table: see text]
3536 Background: We evaluated the prognostic and predictive impact of DNA mutations related to anti-EGFR antibody resistance in patients of the PANAMA trial, which compared Panitumumab (Pmab) and FU/FA versus FU/FA maintenance therapy after Pmab-FOLFOX induction therapy in RAS wild-type (wt) mCRC. Methods: Next generation panel sequencing was conducted on 201 of 248 tumors obtained prior to study inclusion from the full analysis set using the Cancer Hotspot Panel v2 on an Illumina MiSeq system. Hyperselection covered mutations of the following genes: KRAS, NRAS, BRAF, HER2, PTEN, AKT1, PIK3CA. Median progression-free (PFS) and overall survival (OS) since start of maintenance were estimated by Kaplan-Meier and Cox-regression (log rank test). Objective response rates (ORR) of maintenance therapy were compared by Chi-square-test. Results: From 201 tumors, 41 (20.4 %) carried at least one mutation: KRAS: 7 (3.5%), BRAF: 23 (11.4%), PTEN: 4 (2.0%), AKT1: 2 (1.0%), PIK3CA: 12 (6.0%), with 6 tumors harboring co-occuring mutations. No mutations were found in NRAS and HER2. Negative hyperselection (wt for all genes) was associated with (numerically) favourable prognosis in terms of PFS (HR 0.79 (95% CI 0.55 – 1.12), p=0.184), OS (HR 0.61 (95% CI 0.40 – 0.95), p=0.028) and ORR (39.4% vs. 29.3%, p=0.279). The benefit of adding Pmab to FU/FA during maintenance was limited to the hyperselection wt subgroup, with significantly longer PFS (9.9 vs. 6.0 months, 0.64 (95% CI 0,46 – 0.90), p = 0.011), numerically longer OS and significantly higher ORR (49.4% vs 26.6%, p=0.009) compared to FU/FA (Table). Conclusions: Mutations related to resistance concerning anti-EGFR antibodies were detected in 41 of 201 (20.4%) of analysed tumors and associated with a worse prognosis compared to hyperselected wt tumors. Negative hyperselection may aid in the identification of patients with relevant benefit from maintenance therapy including Pmab. [Table: see text]
3587 Background: Carcinoembryonic antigen (CEA) may reflect response to antitumor treatment in metastatic colorectal cancer (mCRC). The predictive value of CEA has not yet been proven for subsequent maintenance therapy. This analysis aims to evaluate the predictive and prognostic value of pre- and post-induction treatment CEA on maintenance with 5-fluoruracil/leucovorin (FU/FA) plus panitumumab (pmab) [arm A] or FU/FA alone [arm B] in RAS wildtype mCRC patients treated within the PanaMa trial. Methods: Patients with CEA measurements (pre- and post-induction therapy) were grouped as normal (both measurements ≤5 ug/l), stable (between +25% and -25%), decreasing (<-25%), and increasing (>+25%) CEA. Survival parameters (overall survival (OS), progression-free survival (PFS) from initiation of maintenance therapy) were expressed by the Kaplan-Meier method and compared by log-rank testing, and Cox regression. The objective response (OR) to maintenance therapy was analyzed by chi-square testing. Results: Out of 248 patients in the in the full analysis set, 245 patients were eligible for CEA analysis. Normal CEA occurred in 58 (23.7%), stable CEA in 16 (6.5%), decreasing CEA in 161 (65.7%), and increasing CEA in 10 (4.1%) patients. In the subgroup of decreasing CEA, there was a significant difference in the prediction of OR between both treatment arms with a better positive predictive value for the pmab-containing maintenance (44.0% vs. 27.5%, p=0.032). Increasing compared to decreasing CEA was associated with unfavourable survival outcome of maintenance irrespective of treatment arm (Table). Conclusions: CEA kinetics during induction therapy appears to have a predictive value for subsequent maintenance, notably pmab-based. Besides that, CEA levels had a significant impact on survival parameters of maintenance irrespective of the addition of pmab to FU/FA. This analysis is limited by the small number of patients in the subgroup of increasing CEA. Clinical trial information: NCT01991873. [Table: see text]
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