Cabozantinib and Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer

Lessons Learned

• Antitumor activity was observed in the study population.
• Dose modifications of cabozantinib improve long-term tolerability.
• Biomarkers are needed to identify patient populations most likely to benefit.
• Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted.

     

Final Analysis of Outcomes and RAS/BRAF Status in a Randomized Phase 3 Study of Panitumumab and Best Supportive Care in Chemorefractory Wild Type KRAS Metastatic Colorectal Cancer

Introduction

Tumor rat sarcoma gene (RAS) status is a negative predictive biomarker for anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). We analyzed outcomes according to RAS and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutational status, and evaluated early tumor shrinkage (ETS) and depth of response (DpR) for patients with wild type RAS.

Plasma Dynamics of RAS/RAF Mutations in Patients With Metastatic Colorectal Cancer Receiving Chemotherapy and Anti-EGFR Treatment

Background

RAS and RAF mutations in colorectal cancer (CRC) hold value in precision medicine. Liquid biopsy is an alternative to tumor tissue biopsy, and circulating tumor DNA (ctDNA) has been intensively investigated, but the clinical relevance of RAS and RAF mutations in plasma is yet to be determined. This study aimed to investigate the clinical aspects of RAS/RAF mutations during combination treatment.

Multicenter Single-Arm,Two-Stage Phase 2 Study of Panitumumab in Patients With Cetuximab-Refractory Metastatic Colorectal Cancer: The PACER Trial

PurposeTo assess whether panitumumab is active in patients with cetuximab-refractory metastatic colorectal cancer (mCRC).Patients and MethodsEligible patients had pretreated RAS (renin–angiotensin system) wild-type mCRC that progressed after cetuximab treatment, after having shown either objective response or stable disease. A minimax two-stage design was applied, with progression-free rate at 2 months as the primary end point. At least 12 of 28 and 21 of 41 successes at the first and second stage, respectively, were required for a positive result. Panitumumab 6 mg/kg was provided every 2 weeks, until progression or unacceptable toxicity.ResultsOverall, 52 patients with KRAS (Kirsten rat sarcoma viral oncogene) wild-type disease were enrolled, but 11 were found to have mutated disease after all-RAS retesting. Among 41 eligible patients, median time since diagnosis was 38 months, and 71% experienced an objective response to previous cetuximab. First stage was passed with 12 of 28 patients alive without progression at 2 months. At the second stage, 17 of 41 patients were alive without progression at 2 months. At a median follow-up of 21.8 months, 35 patients experienced disease progression, and 26 died. Median progression-free survival was 2.1 months (95% confidence interval, 1.8-3.6) and median overall survival 6.8 months (95% confidence interval, 4.6-16.6). Most of the patients experienced no adverse reactions; 25% of patients had grade 3 rash.ConclusionAccording to our study design, panitumumab was not effective in patients with cetuximab-refractory RAS wild-type mCRC.     

An Update on the Biology of RAS/RAF Mutations in Colorectal Cancer

Deaths caused by colorectal cancer (CRC) are among the leading causes of cancer-related death in the United States and around the world. Approximately 150,000 Americans are diagnosed with CRC each year and around 50,000 will die from it. Mutations in many key genes have been identified that are important to the pathogenesis of CRC. Among the genes mutated in CRC, RAS and RAF mutations are common events. Both RAS and RAF are critical mediators of the mitogen-activated protein kinase (MAPK) pathway that is involved in regulating cellular homeostasis, including proliferation, survival, and differentiation. In this review, we provide a historical perspective and update on RAS/RAF mutations as related to colorectal cancer. Additionally, we will review recent mouse models of RAS and RAF mutations that have an impact on CRC research.     

A Phase I Clinical Trial of Trametinib in Combination with TAS-102 in Patients with Chemotherapy-Resistant RAS-Mutated (PIK3CA/PTEN-Wild Type) Metastatic Colorectal Cancer

PurposeWe conducted a phase I study to evaluate the maximum tolerated dose (MTD), safety, and efficacy of trametinib in combination with TAS-102 in patients with chemotherapy-refractory KRAS-mutant, wild-type PIK3CA/PTEN metastatic colorectal cancer (mCRC).MethodsA 3+3 dose de-escalation single arm phase I clinical trial was performed in patients with chemorefractory mCRC without priorTAS-102 exposure. Patients received fixed dosing of trametinib 2mg oral daily along with de-escalating doses of TAS-102 beginning at 35 mg/m² twice daily on days 1-5 and days 8-12 every 28 days. Primary endpoint was evaluation of MTD.Results25 eligible patients were enrolled in this study. During the dose de-escalation phase, no dose-limiting toxicities (DLT) were observed at the full doses of trametinib/TAS-102 and the MTD was determined to be TAS-102 35 mg/m² orally twice daily on days 1 to5 and days 8 to12 every 28 days with continuous trametinib dosing at 2mg orally daily. No patients achieved a partial or complete response. 5 of 21 evaluable patients (23.81%) achieved a stable disease response. Median PFS was two months (95% confidence interval [CI] 1.70-4.82) while median OS was 7 months (95% CI 6.36-11.48). Treatments were well tolerated with most common grade ≥ 3 adverse events being anemia (20%), neutropenia (12%), leukopenia (8%), diarrhea (8%), rash (4%), and fatigue (4%).ConclusionsTrametinib in combination with TAS-102 demonstrated a manageable safety profile. However, this combination did not achieve meaningful clinical benefit in patients with RAS-mutated PIK3CA and PTEN wild-type refractory mCRC. Clinical trial information: NCT03317119.     

Phase II Trial of Erlotinib and Capecitabine for Patients with Previously Untreated Metastatic Colorectal Cancer

BackgroundThis Simon 2-stage phase II trial was designed to document antitumor activity of capecitabine in combination with erlotinib in patients with previously untreated metastatic colorectal cancer (CRC).Patients and MethodsTime to tumor progression, objective response rate, and time to treatment failure were to be assessed. Secondary objectives included determination of toxicity. This trial was closed prematurely because of slower-than-expected accrual. Thirteen patients were enrolled, and all are off protocol treatment at the time of this report.ResultsNotably, 4 subjects discontinued therapy because of adverse events. Of 10 evaluable patients, 1 attained a complete response, 1 attained a partial response, 3 had stable disease, and 5 had progressive disease. Median time to disease progression was 21 weeks, with a range of 8–85 weeks. Overall survival ranged from 12 weeks to 182 weeks, with a median of 76 weeks.ConclusionThe toxicities and challenge to complete accrual observed in this trial are consistent with the experience of others attempting to develop erlotinib as part of combination treatment for advanced CRC.     

Phase I/II Trial of Vinorelbine and Sorafenib in Metastatic Breast Cancer

PurposeWe investigated the efficacy and toxicity of sorafenib, a multikinase inhibitor of vascular endothelial growth factor receptor tyrosine kinase, in combination with vinorelbine therapy in a phase I/II trial in patients with metastatic breast cancer.Patients and MethodsWe enrolled 11 patients in the phase I portion to determine the maximum tolerated dose (MTD) of the combination, followed by 35 extra patients treated at the MTD in phase II. The median age of patients was 54 years old (range, 31-72 years old). Tumors were estrogen receptor and progesterone receptor (ER/PR) positive in 54% (22/54) of patients, and triple negative (ER⁻, PR⁻, HER2⁻) in 41% (17/54) of patients. Of all patients, 22% received sorafenib and vinorelbine as first-line therapy, 37% as second-line therapy, and 41% as third-line therapy.ResultsIn total, 41 patients were treated at the MTD (6 during phase I; 35 in phase II). The observed 44% 4-month progression-free survival rate was similar to the estimated historical rate of 43% with vinorelbine treatment. The combination was tolerated with expected toxicities. Patients treated at the MTD who had received prior bevacizumab treatment received a median of 1.5 cycles (range, 1-10 cycles) compared with a median of 5 cycles (range, 2-12 cycles) for patients without prior bevacizumab treatment.ConclusionFurther evaluation of vinorelbine and sorafenib in bevacizumab-naive patients may be of interest if specific biomarkers guiding patient selection can be identified.     

Relationship Between Tumor Response and Tumor-Related Symptoms in RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses From 3 Panitumumab Trials

BackgroundThere is no standardized assessment of symptomatic events in metastatic colorectal cancer (mCRC) despite disease symptoms that affect treatment decisions. Data from 3 first-line panitumumab in mCRC trials were retrospectively analyzed to assess whether early tumor shrinkage (ETS) and depth of response (DpR) were associated with time to occurrence of tumor-related symptoms.Patients and MethodsPatients with RAS wild-type mCRC from PRIME, PEAK, and Study 314 were included. ETS was defined as a reduction of ≥ 30% in the sum of the longest diameters of lesions at 8 weeks. DpR was calculated as maximum percentage change in tumor size from baseline to nadir. The proportion of patients who developed symptoms (including a composite symptomatic endpoint) during study treatment was calculated. This study was registered at ClinicalTrials.gov as PRIME (NCT00364013), PEAK (NCT00819780), and Study 314 (NCT00508404).ResultsOverall, data of 659 patients were analyzed. Onset of symptoms was delayed in patients with ETS ≥ 30% versus ETS < 30% and in patients with greater DpR. In patients with symptoms at baseline who experienced ETS ≥ 30%, overall survival was similar to that seen for patients without symptoms at baseline.ConclusionBoth ETS and DpR were associated with delayed onset of symptoms in RAS wild-type mCRC patients. Treatments with high cytoreductive potential may delay symptom development.     

Panitumumab with Irinotecan/Leucovorin/5-Fluorouracil for First-Line Treatment of Metastatic Colorectal Cancer

PurposePanitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor and is indicated for patients with metastatic colorectal cancer (mCRC) who have experienced disease progression after standard chemotherapy. We conducted this phase II study to assess the ability of panitumumab to be administered with first-line irinotecan-containing regimens in patients with mCRC.Patients and MethodsThis was a 2-part multicenter study of panitumumab 2.5 mg/kg weekly with irinotecan, 5-fluorouracil (5-FU), and leucovorin. Part I used bolus 5-FU (IFL), and part 2 used infusional 5-FU (FOLFIRI). Tolerability (measured by grade 3/4 diarrhea) was the primary endpoint. Objective response, progression-free survival, overall survival, and safety were also examined.ResultsNineteen patients in part I and 24 patients in part 2 received panitumumab plus chemotherapy. Grade 3/4 diarrhea occurred in II patients (58%) in part I and 6 patients (25%) in part 2. All patients had a skin-related toxicity (no grade 4 events). Objective response rates were 46% in part I and 42% in part 2. Disease control rates were 74% in part I and 79% in part 2. Median progression-free survival (95% confidence interval) was 5.6 months (4.4–8.3 months) for part I and 10.9 months (7.7–22.5 months) for part 2. Median overall survival (95% confidence interval) was 17 months (13.7 months to not estimable) for part I and 22.5 months (14.4 months to not estimable) for part 2.ConclusionIn patients with mCRC, panitumumab/IFL was not well tolerated. Panitumumab/FOLFIRI was well tolerated, showed promising activity, and is undergoing further investigation.     

RAS突变型转移性结直肠癌的精准治疗

转移性结直肠癌(mCRC)是一种异质性疾病,临床表现和分子分型差异大.目前,mCRC在治疗前需要常规行大鼠肉瘤病毒(RAS)基因检测.RAS突变状态与患者预后显著相关并能预测抗表皮生长因子受体(EGFR)治疗的疗效,然而仍缺乏针对RAS靶点的特异性治疗手段.既往研究表明直接抑制RAS蛋白带来的临床获益非常有限,最近报道...     

Rationale and Study Design of the PARERE Trial: Randomized phase II Study of Panitumumab Re-Treatment Followed by Regorafenib Versus the Reverse Sequence in RAS and BRAF Wild-Type Chemo-Refractory Metastatic Colorectal Cancer Patients

BackgroundA recent phase II randomized Japanese study reported better survival with regorafenib followed at progression by cetuximab ± irinotecan compared with the reverse standard sequence in chemo-refractory and anti-EGFR-naïve, RAS wild-type (wt) mCRC patients. Nowadays the use of anti-EGFR antibodies is more frequently anticipated to the first-line of therapy especially in patients with left-sided RAS/BRAF wt tumours. However, retrospective analyses and phase II single-arm trials showed promising activity of re-using anti-EGFRs in metastatic colorectal cancer (mCRC) patients who previously achieved benefit from a first-line anti-EGFR-based treatment. Post-hoc analyses of these trials revealed that the detection of RAS mutations in circulating tumour DNA (ct-DNA) at the time of re-treatment may be useful to identify resistant patients.Patients and MethodsPARERE (NCT04787341) is a prospective, open label, multicentre phase II study in which 214 RAS/BRAF wt chemo-refractory mCRC patients with previous benefit from first-line anti-EGFR-based treatment and RAS/BRAF wt ct-DNA in the liquid biopsy collected at the time of inclusion will be randomized in a 1:1 ratio to receive panitumumab followed after progression by regorafenib versus the reverse sequence. Primary endpoint is overall survival. Secondary endpoints are 1st-progression free-survival (PFS), 2nd-PFS, time to failure strategy, objective response rate, and safety.Aim of the studyThe aim of this study is to validate the role of anti-EGFR retreatment and its proper placement in the therapeutic route of mCRC patients selected according to the analysis of ct-DNA in liquid biopsy. Results are expected at the end of 2023.     

Phase I Trial of Regorafenib,Hydroxychloroquine, and Entinostat in Metastatic Colorectal Cancer

BackgroundThe antiangiogenic tyrosine kinase inhibitor regorafenib provides a survival benefit in patients with previously treated metastatic colorectal cancer (CRC). Antiangiogenic therapy causes hypoxic stress within tumor cells, which activates autophagy as a survival mechanism. The histone deacetylase inhibitor (HDAC) entinostat increases dependence on autophagy through epigenetic mechanisms. Hydroxychloroquine (HCQ) blocks autophagy by blunting lysosomal acidification. We hypothesized that HCQ and entinostat would be tolerable with regorafenib and potentiate the antitumor response.MethodsThis was a 3+3 phase I trial of HCQ and entinostat with regorafenib in patients with metastatic CRC. The primary objective was safety, and the secondary objective was clinical efficacy.ResultsTwenty patients received study therapy. Six evaluable patients were enrolled at each of the three planned dose levels, one patient at an intermediate dose level, and one additional patient withdrew consent after 4 days to receive treatment closer to home. One dose-limiting toxicity was noted in the study at dose level 2 (grade 3 fatigue). Seven patients discontinued therapy due to related toxicities; rapid weight loss was near universal, with a median weight loss of 4.4 kg (range 1.5-12.2 kg) in the first 2 weeks of treatment. No objective responses were observed.ConclusionThe combination of regorafenib, HCQ, and entinostat was poorly tolerated without evident activity in metastatic CRC.ClinicalTrials.gov Identifier {"type":"clinical-trial","attrs":{"text":"NCT03215264","term_id":"NCT03215264"}}NCT03215264     

A Prospective,Multicenter Phase II Study of the Efficacy and Feasibility of 15-minute Panitumumab Infusion Plus Irinotecan for Oxaliplatin- and Irinotecan-refractory,KRAS Wild-type Metastatic Colorectal Cancer (Short Infusion of Panitumumab Trial)

Background

In some recently updated clinical guidelines, the fully humanized monoclonal antibody panitumumab, combined with irinotecan, has been recommended as an optional third-line chemotherapy for KRAS wild-type metastatic colorectal cancer (mCRC). The present prospective, multicenter phase II study evaluated the effectiveness and safety of short 15-minute panitumumab infusions.

A Phase II Trial of FOLFOX6 and Cetuximab in the First-line Treatment of Patients With Metastatic Colorectal Cancer

IntroductionThis phase II trial evaluated the efficacy and safety of cetuximab combined with FOLFOX6 (leucovorin [LV] 5-fluorouracil [5-FU]/oxaliplatin) in the first-line treatment of patients with advanced or metastatic colorectal cancer.Patients and MethodsPatients with locally advanced or metastatic CRC who had received no previous therapy for advanced disease were treated with cetuximab at a loading dose of 400 mg/m² followed by 250 mg/m² weekly and a FOLFOX6 regimen every 2 weeks consisting of oxaliplatin 85 mg/m², LV 400 mg/m², and 5-FU bolus 400 mg/m² followed by 5-FU continuous infusion 2400 mg/m² over 46 hours.ResultsA total of 82 eligible patients were enrolled; epidermal growth factor receptor expression was positive in 67 patients. The overall response rate was 44.8%. In addition, 30 patients (44.8%) in the evaluable population experienced stable disease. Median time to progression or death was 9.3 months (95% CI, 7.0-11.3 months), and median survival was 21.7 months (95% CI, 17.5-27.8 months). Patients who experienced skin toxicity had a statistically significant and longer median survival time than those patients with no skin toxicity (P = .0001). The most commonly observed toxicities were neutropenia (65%), fatigue (56.3%), diarrhea (53.8%), nausea (50%), acneiform rash (41.3%), and stomatitis (35%).ConclusionOur results demonstrate that cetuximab can be safely combined with FOLFOX6 for the first-line treatment of patients with metastatic CRC (mCRC). The efficacy parameters are similar to other first-line regimens in mCRC. Because of the emergence of KRAS as a predictive marker, this regimen has promise in KRAS wild-type mCRC.     

A Phase II Study of FOLFOXIRI Plus Panitumumab Followed by Evaluation for Resection in Patients With Metastatic KRAS Wild‐Type Colorectal Cancer With Liver Metastases Only

Lessons Learned

• This regimen is a viable option for patients with liver-only metastatic colorectal cancer.
• Enrollment criteria for future studies should include testing for the newly identified KRAS mutations.

Background.

Patients with liver-only metastatic colorectal cancer (mCRC) who are not candidates for potentially curative resection may become resectable with more aggressive chemotherapy regimens. In this nonrandomized trial, we evaluated folinic acid, 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) plus the epidermal growth factor receptor inhibitor panitumumab as first-line treatment for KRAS wild-type mCRC with liver-only metastasis.

Methods.

Patients received FOLFOXIRI (5-FU, 3,200 mg/m², 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m² i.v.; irinotecan, 125 mg/m²; oxaliplatin, 85 mg/m² i.v.) and panitumumab (6 mg/kg i.v.) on day 1 of 14-day cycles. Patients were restaged and evaluated for surgery every four cycles. Planned enrollment was originally 49 patients. The primary endpoint was objective response rate.

Results.

Fifteen patients (median age: 55 years; 87% male) received a median 6 cycles of treatment (range: 1–33 cycles); 10 patients (67%) were surgical candidates at baseline. Twelve patients were evaluable for clinical response; 9 (60%) achieved partial response. Ten patients underwent surgery; all had complete resections and pathologic partial response. Treatment-related grade 3 adverse events included diarrhea (33%) and rash (20%). Enrollment was halted because of emerging data on expanded KRAS/NRAS mutations beyond the region we initially examined, and the potential for negative interaction with oxaliplatin-based therapy. Eight patients underwent expanded KRAS/NRAS analysis outside exon 2; no additional mutations were found.

Conclusion.

KRAS/NRAS mutations outside the region tested in this study were recently shown to be associated with inferior survival on similar treatment regimens. Therefore, this trial was stopped early. This regimen remains a viable option for patients with liver-only mCRC in the KRAS/NRAS wild-type population. Enrollment criteria on future studies should include testing for the newly identified mutations.