Background: Although Chemoradiation (CRT) is the curative treatment for SCCAC, many patients present primary resistance. Since it is a rare tumor, response predictors remain unknown. Methods: We performed a prospective cohort study to evaluate biomarkers associated with CRT response, progression-free survival (PFS), and overall survival (OS). The primary endpoint was response at 6 months (m). Tumor DNA and HPV were analyzed by next-generation sequencing, while KI-67 and PD-L1 by immunohistochemistry in tumor tissue. Results: Seventy-eight patients were recruited between October/2011 and December/2015, and 75 were response evaluable. The median age was 57 years, 65% (n=49) were stage III and 12% (n=9) were HIV positive (HIV+). At 6m, 62.7% (n=47) presented CR. On multivariate analyses, stage II patients were 4.7 more likely to achieve response than stage III (OR, 4.70; 95%CI, 1.36-16.30; p=0.015). HIV+ was associated with a worse response (OR, 5.72; 95%CI, 2.5-13.0; p<0.001). 5-year PFS and OS rates were 63.3% and 76.4%, respectively, with a median follow up of 66m. On multivariate analyses, older age (HR 1.06, p=0.022, 95%IC 1.01-1.11) and absence of CR at 6m (HR 3.36, p=0.007, 95%IC 1.39-8.09) were associated with inferior OS. The 5-year OS rate was 62.5% in HIV+ group compared to 78% among HIV- pts, although this difference was not statistically significant (p=0.4). PIK3CA, MET and TP53 mutations, HPV, Ki-67 expression, and PD-L1 expression, were not associated with PFS and OS. Conclusions: Clinical stage III and HIV+ were associated with worse response to CRT at 6m. The absence of CR was the main factor associated with poor 5-year OS.
Background Regorafenib is a multikinase inhibitor with antiangiogenic effects that improves overall survival (OS) in metastatic colorectal cancer (mCRC) after failure of standard therapies. We investigated the efficacy and safety of regorafenib in antiangiogenic therapy‐naïve chemotherapy‐refractory advanced colorectal cancer. Patients and Methods This single‐center, single‐arm, phase IIb study (NCT02465502) enrolled adults with mCRC whose disease had progressed on, or who were intolerant to, standard therapy, but who were antiangiogenic therapy‐naïve. Patients received regorafenib 160 mg once daily for 3 weeks per 4‐week cycle. The primary endpoint was progression‐free survival (PFS) rate at week 8. Results Of 59 treated patients, almost half had received at least four prior lines of therapy. Patients received a median of 86% of the planned dose. The week 8 PFS rate was 53% (95% confidence interval [CI], 39.1–64.3); median PFS was 3.5 months (95% CI, 1.8–3.6). Median OS was 7.4 months (95% CI, 5.3–8.9). Tumor response (RECIST version 1.1) was 2%, and metabolic response rate (criteria from the European Organisation for Research and Treatment of Cancer) was 41%. The most frequently reported regorafenib‐related grade ≥3 adverse events were hypertension (36%), hand–foot skin reaction (HFSR, 25%), and hypophosphatemia (24%). There were no regorafenib‐related deaths. An exploratory analysis showed that patients with grade ≥2 HFSR had longer OS (10.2 months) with regorafenib treatment versus those with grades 0–1 (5.4 months). Conclusion These findings support the antitumor activity of regorafenib in antiangiogenic‐naïve patients with chemotherapy‐refractory mCRC. Implications for Practice The multikinase inhibitor regorafenib improved overall survival in the phase III CORRECT and CONCUR trials in heavily pretreated patients with treatment‐refractory metastatic colorectal cancer (mCRC). Exploratory subgroup analysis from CONCUR suggested that regorafenib treatment prior to targeted therapy (including bevacizumab) may improve outcomes. In this single‐center, single‐arm phase IIb study, regorafenib demonstrated antitumor activity in 59 antiangiogenic‐naïve patients with chemotherapy‐refractory mCRC. Further studies should assess the efficacy of regorafenib in this patient population, as well as explore the reasons behind improved outcomes among patients who had a metabolic response and those who developed hand–foot skin reaction.
4053 Background: Chemoradiation (CRT) is a curative treatment for SCCAC. However, some patients (pts) present primary CRT resistance. As a rare tumor, there is a lack of prospective studies of prognostic factors in this setting. Methods: This prospective cohort study was aimed to evaluate predictive biomarkers (Ki-67, PD-L1, Human papillomavirus (HPV), HIV status, and tumor DNA mutations) in SCCAC. We published the 6 months (m) response rate (RR) of this cohort showing that HIV- were 5.7 times more likely to achieve response 6m post CRT (OR 5.72, CI 95% 2.5-13.0, P < 0.001). Now we report the long-term follow-up results of 5-year progression-free survival (PFS) and overall survival (OS). Eligible pts had T2-4/N0-3/M0 disease and were candidates to standard CRT. DNA mutations were analyzed by next-generation sequencing (NGS). HPV positivity was tested by PapilloCheck Test. KI-67 and PD-L1 were evaluated by immunohistochemistry. Results: 78 pts were recruited from Jan/2011 to Dec/2015. 75 were evaluable for PFS and OS. The median age was 57 years; 49 (65%) were stage III, and 9 (12%) were HIV+. HPV was evaluated in 67 and found in 47 (70.1%); HPV16 was the most common. PD-L1 was tested in 61; 10 (16.4%) had positive expression > 1%. Ki-67 was performed in 65, with a median of 50% (range 1-90%). The median follow up is 66m. 5-year PFS and OS rates were 63.3% (95% CI 51.2-73.2%) and 76.4% (95% CI 64.8-84.6%), respectively. In a multivariate analysis, age (HR 1.06, P = 0.022, IC 95% 1.01-1.11) and absence of complete response at 6m (HR 3.36, P = 0.007, IC 95% 1.39-8.09) was associated with inferior OS. The OS rate was 62.5% in HIV+ group (95% CI 22.9-86%) in comparison with 78% (95% CI 65.7-86.3%) among HIV- pts, although this difference was not statistically significant (P = 0.400). A tendency to inferior OS was observed among pts with p53 codon 72 polymorphism (HR 2.83, P = 0.181, 95% CI 0.61-13.02). Other tumor mutations, HPV, Ki-67 expression, and PD-L1 expression, were not associated with PFS and OS. Conclusions: HIV- pts were 5.7 times more likely to achieve response 6m post CRT. The absence of complete response at 6m was the main factor associated with poor 5-year OS. New strategies of follow up and complementary treatment should be studied in late responders and HIV+ pts to ensure the success of curative treatment. Clinical trial information: 36211 .
3577 Background: While chemoradiation (CRT) is a curative treatment for SCCAC, many patients (pts) present primary resistance. As a rare tumor, the predictors of response in this setting remain unknown. Methods: Prospective cohort study aimed to evaluate predictive biomarkers (Ki-67, PD-L1, Human papillomavirus (HPV), HIV status and mutations in tumoral DNA) associated with complete response (CR) following standard CRT for localized SCCAC. Eligible pts had T2-4/N0-3/M0 disease and were candidates to standard CRT. CR at 6 months (m) measured by RECIST 1.1 was the primary endpoint. DNA mutations were analyzed by next-generation (NGS) TruSight Tumor26 panel. HPV positivity was tested by PapilloCheck Test. KI-67 and PD-L1 were evaluated by immunohistochemistry. Results: 78 pts were recruited from Jan/2011 to Dec/2015. 75 were evaluable for response. Median age 57 years; 49 (65%) were stage III, and 9 (12%) were HIV+. At 6m 47 (62.7%) had CR, 18 (24%) partial response (PR) and 10 (13.3%) disease progression. HPV was evaluated in 67 and found in 47 (70.1%), the majority HPV16. PD-L1 was tested in 61, 10 (16.4%) had > 1% positive expression. Ki-67 was performed in 65, a median was 50% (1-90%) per patient. Clinical stage, HIV status, median KI-67, HPV and PD-L1 positivity, and treatment interruption were tested as predictive factors of CR in 6m by logistic regression. On multivariable analyses, ECII patients were 4.7 more likely to achieve CR than ECIII (OR 4.70 CI95%1.36-16.30; p = 0.015). HIV was borderline significant (OR 2.53 CI95% 0.9-7.1; p = 0.079). Analyzing the patients with PR and CR HIV+ was significantly associated with poor response. Patients HIV- were 5.7 more likely to achieve CR or PR (OR 5.72 CI95%2.5-13.0; p < 0.001). 25 patients had tumor samples proper for NGS, 17 had at least one pathogenic mutation. The most common mutated genes were PIK3CA and MET in 6. There was no differences in CR rates according to MET (50% vs 47.3%, p = 1) or PIK3CA (33.3% vs 47.3%, p = 0.6) mutation status. TP53 codon 72 polymorphism was present in 72% (n = 18) and was not associated with CR (44% VS 57%, p = 0.6). Conclusions: Our study suggests that HIV+ pts are less responsive to CRT.
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