New Data Reported on Vemurafenib, Vitamin D, Selective Internal Radiotherapy, and Circulating Tumor DNA in Colorectal Cancer


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RESULTS OF the IDEA trial, which showed that some patients with stage III low-risk colon cancer may require less oxaliplatin therapy (see the June 25 issue of The ASCO Post), were among the findings highlighted at the 2017 ASCO Annual Meeting Plenary Session. Other studies of interest in colorectal cancer presented this year in Chicago are summarized in the following roundup. 

Outcomes for BRAF-Mutated Disease Improved With Vemurafenib 

METASTATIC COLORECTAL CANCER patients with BRAF V600E mutations derived substantial benefit from the addition of the BRAF inhibitor vemurafenib (Zelboraf) to chemotherapy, in a study reported by Scott Kopetz, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston.

“The combination of vemurafenib, cetuximab [Erbitux], and irinotecan met its primary endpoint, demonstrating improved progression-free survival in patients with BRAF V600E colorectal cancer. This combination represents a new treatment for metastatic BRAF V600E–mutated tumors,” Dr. Kopetz said. 

BRAF V600E mutations are present in 7% of metastatic colorectal cancers and are associated with aggressive biology, short overall survival, and limited response to standard chemotherapy. Vemurafenib, a BRAF inhibitor, has limited activity as a single agent but has demonstrated synergy when the epidermal growth factor receptor (EGFR) is inhibited. 

The study included 99 patients with BRAF V600E mutations and wild-type RAS, previously treated for metastatic disease. They were randomized to receive cetuximab plus irinotecan with or without vemurafenib (960 mg twice daily). The primary endpoint was progression-free survival. 


“The addition of vemurafenib to cetuximab/irinotecan showed activity [in BRAF-mutated disease], even after progression.”
— Scott Kopetz, MD, PhD

Median progression-free survival was 4.3 months in the vemurafenib arm vs 2.0 months with chemotherapy alone, a 52% reduction in risk (P = .001). Response rates (16% vs 4%) and disease control rates (67% vs 22%) were also greatly improved (P = .001). All subgroups had at least a 40% reduction in progression with vemurafenib, Dr. Kopetz reported. 

Almost half the control arm ultimately crossed over to receive vemurafenib plus chemotherapy. Their median progression-free survival was 5.8 months, median overall survival was 12.1 months, and disease control rate was 72%. “The addition of vemurafenib to cetuximab/irinotecan showed activity, even after progression,” he said. 

Overall survival analysis showed a trend for a reduction in mortality, but this analysis was limited by the high rate of crossover. Median survival was 9.6 vs 5.9 months, a 27% reduction in risk (P = .19) with vemurafenib. 

The triplet was associated with a higher rate of side effects, most notably more anemia, neutropenia, and nausea. 

High-Dose Vitamin D Improves Outcomes in Metastatic Disease 

HIGH-DOSE vitamin D was associated with prolonged progression-free survival in metastatic colorectal patients in the SUNSHINE trial, reported at the ASCO Annual Meeting by Kimmie Ng, MD, MPH, of Dana-Farber Cancer Institute, Boston.2 

Vitamin D has antineoplastic properties, and its receptor is expressed in colorectal cancer cells. Higher plasma 25(OH)D levels have been associated with improved survival in patients with colorectal cancer. 

The SUNSHINE trial aimed to validate a subset analysis of the CALGB/SWOG 80405 study, which compared the efficacy of cetuximab vs bevacizumab (Avastin) when added to chemotherapy and found no difference in survival between the arms. However, in an analysis of 1,043 patients by baseline 25(OH)D level, patients in the highest quintile had improved overall survival (adjusted hazard ratio [HR] = 0.065; P = .001) and progression-free survival (adjusted HR = 0.079; P = .01). 


“In combination with first-line chemotherapy, high-dose vitamin D3 supplementation significantly improved progression-free survival in metastatic colorectal cancer patients and did not lead to any added toxicity.”
— Kimmie Ng, MD, MPH

The effect of vitamin D was explored prospectively in the SUNSHINE trial of 139 previously untreated metastatic colorectal cancer patients, randomized to receive FOLFOX (leucovorin, fluorouracil [5-FU], oxaliplatin) and bevacizumab plus (1) vitamin D3 at 400 IU/d (the control arm) or (2) the high-dose arm receiving vitamin D3 at 8,000 IU/d for 2 weeks (loading dose) followed by vitamin D3 at 4,000 IU/d (maintenance dose). 

“High-dose vitamin D resulted in improved progression-free survival,” Dr. Ng reported. Median progression-free survival was 13.1 months in the high-dose arm and 11.2 months in the control arm (HR = 0.69; P = .04). Use of high-dose vitamin D3 remained significant in the multivariate analysis (HR = 0.67; P = .02). 

“This is the first completed, randomized, double-blinded, controlled clinical trial of vitamin D supplementation in colorectal cancer patients. In combination with first-line chemotherapy, high-dose vitamin D3 supplementation significantly improved progression-free survival in metastatic colorectal cancer patients and did not lead to any added toxicity,” Dr. Ng said. 

Selective Internal Radiotherapy Delivers No Benefit in Liver Metastases 

PATIENTS WITH LIVER-ONLY or liver-dominant metastatic colorectal cancer may not benefit from selective internal radiotherapy plus chemotherapy, according to a meta-analysis of three randomized clinical trials.3 Despite increasing the likelihood of radiologic response and prolonging liver-specific progression-free survival, selective internal radiotherapy added to first-line chemotherapy did not delay progression or improve survival, according to Ricky A. Sharma, MA, MB, BChir, PhD, of the University College London, United Kingdom. 

Ricky A. Sharma, MA, MB, BChir, PhD

Ricky A. Sharma, MA, MB, BChir, PhD

The findings came from a pooled analysis of prospective data from 1,103 patients with unresectable liver metastases included in the FOXFIRE, SIRFLOX, and FOXFIRE-Global trials. Patients were randomly assigned to receive FOLFOX in combination with one round of selective internal radiotherapy using yttrium-90 resin microspheres or FOLFOX alone. All patients also could have received a biologic agent (bevacizumab or cetuximab) in combination with FOLFOX, which was started upfront in the FOLFOX control arm and after four or more cycles in the FOLFOX/radiotherapy arm to avoid possible adverse interactions with the radiation. 

After a median follow-up of 43.3 months, there was no significant difference in overall survival (hazard ratio [HR] = 1.04; P = .609) or progression-free survival (HR = 0.90; P = .108). The selective internal radiotherapy arm was superior, however, with respect to liver-specific progression-free survival (HR = 0.51; P < .001) and best radiologic response rate (HR = 1.52; P < .001), though these advantages were offset by more extrahepatic progression or death in the radiotherapy arm (HR = 1.76; P < .001). 

One possible explanation for the lack of radiotherapy benefit may be that fewer patients in the FOLFOX/radiotherapy arm received bevacizumab during the study (36% vs 47%), and fewer received subsequent systemic therapy (approximately 68% vs 74%), Dr. Sharma suggested. 

An intriguing finding from the subgroup analysis was that patients with right-sided tumors did have a marked improvement in survival when selective internal radiotherapy was added to FOLFOX (HR = 0.67, 95% confidence interval = 0.48–092), though this finding is exploratory and needs to be validated in other data sets, he cautioned.


“We often see our patients with metastatic colon cancer succumb to liver disease…. If we were just able to control the liver, perhaps that would translate into an improvement in survival. In this study, this was not the case.”
— Andrea Cercek, MD

Discussant Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center, New York, noted that this study is the largest trial of radiation therapy in metastatic colon cancer and took more than a decade to complete. While it was a “great effort,” she said, the conclusion is that selective internal radiotherapy has no role in first-line therapy for metastatic colorectal cancer. 

“We often see our patients with metastatic colon cancer succumb to liver disease. We believe that it’s important to treat the liver, and if we were just able to control the liver, perhaps that would translate into an improvement in survival,” Dr. Cercek said. “In this study of more than 1,000 patients, this was not the case.” 

Circulating Tumor DNA Prognostic for Disease Recurrence 

SEVERAL POSTERS at the ASCO meeting evaluated the prognostic power and utility of circulating tumor DNA, one in rectal cancer and one in patients with resected liver metastases. 

Australian investigators, led by Jeanne Tie, MD, of the Walter and Eliza Hall Institute of Medical Research, evaluated circulating tumor DNA as a potential means of guiding adjuvant chemotherapy decision-making in locally advanced rectal cancer.4 In 159 patients, they detected circulating tumor DNA at diagnosis in 77%, after neoadjuvant chemoradiotherapy in 8%, and after resection in 12%. Baseline pretreatment circulating tumor DNA was not associated with recurrence, but posttreatment circulating tumor DNA was. Based on postoperative circulating tumor DNA, the investigators stratified patients into groups at very high risk and at low risk of recurrence. They found the measurement was predictive of recurrence, irrespective of the use of adjuvant chemotherapy. 

Hazard ratios were 6.5 (P < .001) for patients with detectable circulating tumor DNA after chemoradiotherapy and 11.0 (P < .001) for those with detectable circulating tumor DNA after surgery. The study also confirmed the prognostic significance of known pathologic features. 


“The detection of [circulating tumor DNA] following liver resection may allow personalization of both adjuvant treatment and surveillance.”
— Michael J. Overman, MD, and colleagues

“Circulating tumor DNA analysis remains strongly predictive of recurrence among patients with lower risk (achieving pathologic complete response) and higher risk (node-positive) disease,” the authors noted. 

A study from The University of Texas MD Anderson Cancer Center evaluated postoperative circulating tumor DNA using a colorectal cancer next-generation sequencing panel (Illumina HiSeq2500 with a 120,000× sequencing depth) that does not require knowledge of known patient mutations. In 58 patients undergoing curative-intent hepatic metastasectomies, postoperative circulating tumor DNA positivity was strongly associated with disease recurrence, according to Michael J. Overman, MD, and colleagues.

Median recurrence-free survival was 7.6 months when circulating tumor DNA was detected and 15.8 months for undetected circulating tumor DNA (P = .004). Two-year recurrence-free survival was 9% and 43%, respectively. 

“The detection of [circulating tumor DNA] following liver resection may allow personalization of both adjuvant treatment and surveillance,” the authors concluded. ■

DISCLOSURE: For full disclosures of the study authors, see the respective abstracts at meetinglibrary.asco.org. 

REFERENCES 

1. Kopetz S, et al: Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). 2017 ASCO Annual Meeting. Abstract 3505. Presented June 5, 2017. 

2. Ng K, et al: SUNSHINE: Randomized double-blind phase II trial of vitamin D supplementation in patients with previously untreated metastatic colorectal cancer. 2017 ASCO Annual Meeting. Abstract 3506. Presented June 5, 2017. 

3. Sharma RA, et al: Overall survival analysis of the FOXFIRE prospective randomized studies of first-line selective internal radiotherapy in patients with liver metastases from colorectal cancer. 2017 ASCO Annual Meeting. Abstract 3507. Presented June 5, 2017. 

4. Tie J, et al: The potential of circulating tumor DNA to guide adjuvant chemotherapy decision-making in locally advanced rectal cancer. 2017 ASCO Annual Meeting. Abstract 3521. Presented June 3, 2017. 

5. Overman MJ, et al: Circulating tumor DNA utilizing a high-sensitivity panel to detect minimal residual disease post-liver hepatectomy and predict disease recurrence. 2017 ASCO Annual Meeting. Abstract 3522. Presented June 3, 2017.


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