TheraSphere Y-90 Plus Chemo Prolongs PFS, hPFS in Second-Line Metastatic CRC

Mary F. Mulcahy, MD

The addition of TheraSphere™ Yttrium-90 (Y-90) Glass Microspheres to standard-of-care second-line chemotherapy in patients with colorectal cancer liver metastases led to a significant improvement in progression-free survival (PFS) and hepatic PFS (hPFS) over chemotherapy alone, meeting both primary end points of the ongoing EPOCH trial.¹

Results, which were presented during the 2021 ESMO Congress, showed that the median PFS with Y-90 plus chemotherapy was 8.0 months (95% CI, 7.2-9.2) vs 7.2 months (95% CI, 5.7-7.6) with chemotherapy alone (HR, 0.69; 95% CI, 0.54-0.88; P = .0013).

The 6-month PFS rates in the investigative and control arms were 65.2% (95% CI, 58.0%-71.5%) and 55.4% (95% CI, 47.2%-62.8%); at 12 months, these rates were 25.8% (95% CI, 18.9%-33.1%) and 13.2% (95% CI, 7.5%-20.5%), respectively. At 18 months, the PFS rate with Y-90 plus chemotherapy was 16.7% (95% CI, 10.6%-23.9%) and 1.8% (95% CI, 0.2%-8.1%), respectively.

The median hPFS was 9.1 months (95% CI, 7.8-9.7) was Y-90 plus chemotherapy vs 7.2 months (95% CI, 5.7-7.6) with chemotherapy alone (HR, 0.59; 95% CI, 0.46-0.77; P < .0001). In the investigative arm, the 6-, 12-, and 18-month hPFS rates were 70.7% (95% CI, 63.6%-76.6%), 29.8% (95% CI, 22.4%-37.6%), and 19.8% (95% CI, 13.0%-27.6%), respectively. In the control arm, these rates were 55.2% (95% CI, 47.1%-62.7%), 13.5% (95% CI, 7.7%-20.9%), and 1.9% (95% CI, 0.2%-8.3%), respectively.

“EPOCH is the first positive phase 3 global study of Y-90 transarterial radioembolization [TARE] and chemotherapy in the second-line treatment of patients with colorectal liver metastases,” Mary F. Mulcahy, MD, Department of Medicine, Division of Hematology/Oncology, Northwestern University, Lurie Comprehensive Cancer Center, said in a presentation on the data. “This is the first arterial radiotherapy device to demonstrate a statistically significant delay in progression in metastatic CRC.”

Approximately 80% of patients with colorectal liver metastases are not candidates for surgical resection. Locoregional strategies for liver-confined metastases can potentially provide clinically meaningful benefit beyond that of systemic therapy by itself. TARE with Y-90 delivers selective internal radiotherapy with beta-emitting particles transported through the hepatic vasculature into tumor-feeding arteries.

The rationale to evaluate glass-based TARE in the second-line setting is based on the inherent vascularity of hepatic colorectal lesions in the arterial phase. As such, the EPOCH trial was launched.

To be eligible for enrollment, patients needed to be 18 years of age or older, have unresectable unilobar or bilobar disease that is measurable per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, bilirubin ≤1.2 x upper limit of normal, and albumin ≥3.0 gm/dL. Patients also needed to be able to receive second-line irinotecan or oxaliplatin-based chemotherapy.

If patients had a history of prior arterial or radiotherapy to the liver, clinically evidence ascites, unresolved toxicities from frontline therapy, confirmed extrahepatic disease, and contraindication for hepatic angiography, they were excluded.

A total of 428 patients were randomized 1:1 to receive either Y-90 plus chemotherapy with or without targeted therapy (n = 215) or chemotherapy with or without targeted therapy (n = 213). The chemotherapy was either irinotecan or oxaliplatin-based chemotherapy.

Stratification factors included disease (unilobar vs bilobar), KRAS status (yes vs no), and frontline therapy (irinotecan- vs oxaliplatin-based).

Follow-up was done every 8 weeks until progressive disease or hepatic disease progression or death. Last, patients will undergo survival follow-up.

The primary end points of the trial were PFS and hPFS adjudicated by blinded independent central review (BICR). For the study to be successful, the PFS and/or the hPFS must be statistically significant, defined as 1-sided alpha level .00248. Secondary end points include overall survival, time to symptomatic progression, objective response rate (ORR) and disease control rate by BICR, and time to deterioration in quality of life.

The median age of patients across the arms was 61.5 years, 62.8% were male, 64.5% were from Europe, 58.9% had an ECOG performance status of 0, 83.9% had albumin that was greater than or equal the lower limit of normal. The carcinoembryonic antigen level was 35 ng/mL or higher in 51.7% of patients. Regarding KRAS mutational status, 47.0% of patients had KRAS-mutated disease and 53.1% had KRAS wild-type disease.

Moreover, 81.6% of patients had bilobar disease. Most patients in the investigative and control arms had liver tumor burden that was less than 10%, at 57.7% vs 56.8%, respectively; 25.1% and 22.1% of patients, respectively, had a burden of 10% to 24%, and 13.5% and 13.1% of patients, respectively had a burden that was 25% or higher.

Seventy-one percent of patients across the arms had a maximum liver lesion size of 40 mm or larger, 66.8% had primary tumor in situ, 66.8% had a left side primary tumor, 48.6% had extrahepatic lesions at baseline, and most patients had over 10 lesions.

Eighty-seven percent of patients on the investigative arm received treatment vs 89.7% of those on the control arm. Moreover, 94.4% and 89.7% of patients, respectively, received second-line chemotherapy. In 60.5% and 57.7%, respectively, of these patients, the chemotherapy was irinotecan based, and the mean number of cycles in the investigative and control arms was 9.0 and 9.5, respectively. Oxaliplatin-based chemotherapy was given in 34.0% of those in the Y-90 group vs 31.9% of those in the control group, with a mean number of 8.5 and 8.8 cycles, respectively.

Additionally, 40.9% and 43.7% of patients, respectively, received a biological agent. Among the biologic agents received were aflibercept (Eylea)/ramucirumab (Cyramza), bevacizumab (Avastin), cetuximab (Erbitux), and panitumumab (Vectibix).

The median absorbed dose to perfused volume before progression by investigator determination was 117 Gy (range, 61.7-156.0), and the median time to Y-90 was 25 days (range, 12-90).

Additional data from the trial revealed that key characteristics of interest that were linked with a PFS benefit with Y-90 plus chemotherapy were tumors with a KRAS mutation, hepatic tumor burden of 10% to 24%, less than 3 lesions, left-sided primary tumor, and addition of a biologic agent. Key features linked with a hPFS benefit with Y-90/chemotherapy include tumors with a KRAS mutation, a hepatic tumor burden of less than 25%, less than 3 lesions, left- or right-sided primary tumor, and the addition of a biologic agent.

Y-90 plus chemotherapy elicited an ORR of 34.0% (95% CI, 28.0%-40.5%) vs 21.1% (95% CI, 16.2%-27.1%) with chemotherapy alone. Among the responders in the investigative arm, 0.9% achieved a complete response, 33.0% had a partial response, 45.6% had stable disease, and 12.6% experienced disease progression.

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) were reported in 96.8% and 93.7% of those in the investigative and control arms, respectively. Chemotherapy-related toxicities were experienced by 92.0% of those in the Y-90 group vs 91.3% of those in the chemotherapy-alone group. Adverse device events occurred in 55.1% of those who received Y-90.

Moreover, angiographic procedure-related TEAEs were reported in 29.4% of those who received Y-90/chemotherapy vs 1.0% of those who received chemotherapy alone. TEAEs with Common Terminology Criteria for Adverse Events that were grade 3 or higher were reported in 68.4% and 49.3% of those in the investigative and control arms, respectively.

Serious TEAEs were experienced by 37.4% of those in the Y-90 arm vs 20.8% of those in the control arm. Serious treatment-emergent adverse device events were reported in 10.7% of those on Y-90.

TEAEs resulted in a fatal outcome in 8 patients who received Y-90/chemotherapy and 4 patients who were given chemotherapy alone. Moreover, 12.8% and 12.1% of those on the investigative and control arms, respectively, experienced TEAEs that required chemotherapy discontinuation.

“This is the first arterial radiotherapy device to demonstrate a statistically significant delay of progression in metastatic colorectal cancer,” Mulcahy concluded.

Reference

1. Mulcahy MF, Salem R, Mahvash A, et al. Radioembolization with chemotherapy for colorectal liver metastases: a randomized, open-label, international, multicenter, phase III trial (EPOCH study). Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract LBA21.