Key Trials Seek to Expand on Efficacy, Tolerability of Treatment Regimens in Refractory CRC

Iman Imanirad, MD

The CCTG CO.26, ReDOS, and IMblaze370 trials, although not all positive, are all trials that have shaped approaches to treating patients with advanced refractory colorectal cancer (CRC).

“These are thought-provoking studies that were presented at the 2018 and 2019 Gastrointestinal Cancers Symposium,” said Iman Imanirad, MD, in a presentation during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies.

CCTG CO.26

At the meeting, Imanirad, a medical oncologist at Moffitt Cancer Center, discussed these trials in depth and their impact on patients with refractory metastatic CRC.In the Canadian trial, investigators examined the combination of durvalumab (Imfinzi) and tremelimumab in patients with advanced refractory disease. This combination of CTLA-4 and PD-L1 inhibition resulted in benefit regardless of whether the patient had microsatellite instability-high (MSI-H)/mismatch repair-deficient tumors or microsatellite stability (MSS) disease, said Imanirad.

Patients were randomized 2:1 to receive 1500 mg of durvalumab every 28 days and 75 mg of tremelimumab every month for the first 4 cycles of therapy alongside best supportive care (BSC) every 28 days or BSC alone. Overall survival (OS) served as the primary endpoint of the study, with secondary endpoints of progression-free survival (PFS), objective response rate (ORR), safety, and toxicity.

Patients were well balanced between arms in terms of age, performance status, and prior therapies, added Imanirad. All patients had received irinotecan, and almost all had received 5-fluorouracil and anti-VEGF therapy. Approximately 80% of patients had prior exposure to oxaliplatin. Patients who harbored a RAS wild-type mutation also received anti-EGFR therapy. Notably, more patients enrolled in the experimental arm had KRAS mutations compared with the control arm, and more NRAS mutations were observed in the control arm than were seen in the experimental arm. Approximately two-thirds of patients had also received radiation therapy.

Patient accrual occurred fairly rapidly from August 2016 to June 2017, said Imanirad, during which time 180 patients enrolled on the trial.

Among the intention-to-treat (ITT) population at the time of data cut off in August 2018, 21.8% of patients had stable disease in the investigational arm compared with 6.6% in the control arm.¹ OS favored patients who received the immunotherapy doublet at 6.6 months compared with 4.1 months in the control arm (stratified HR, 0.72; 90% CI, 0.54-0.97; P = .07). Notably, PFS was 1 month worse with the immunotherapy doublet versus BSC (1.8 months vs 1.9 months; stratified HR, 1.01; 90% CI, 0.76-1.34; P = .97).

OS benefit was noted irrespective of subgroup, said Imanirad. Quality of life (QoL) was included as a tertiary endpoint and was assessed based on the EORTC QLQ-C30. “There was no significant difference in QoL as it pertains to the deterioration of the patient’s physical function and global health status,” added Imanirad.

In terms of toxicity, 64% of patients in the investigational arm and 20% of patients in the control arm experienced grade ≥3 adverse events (AEs), the most common of which were fatigue, abdominal pain, and lymphopenia in the investigational arm.

ReDOS

“Durvalumab and tremelimumab improved survival in the phase II study, and there was no adverse impact on QoL,” said Imanirad. “The toxicity profile was in line with previous immunotherapy regimens, and that should be a platform to launch a phase III clinical trial in the refractory setting.”Due to the off-target effects of regorafenib (Stivarga), its toxicity is ill-tolerated by many patients, explained Imanirad. As such, this phase II trial was designed to assess regorafenib in a step-wise manner to see if it could be better tolerated. The proportion of patients who were able to complete 2 cycles of treatment and initiate a third cycle served as the primary endpoint of the trial, with secondary endpoints of OS, PFS, and time to progression.

In the experimental arms, patients with an ECOG performance status of 0 or 1 received 80 mg of regorafenib for the first week of treatment and were escalated every week thereafter by 40 mg, after which they received the standard dose or last best tolerated dose. Patients in the control arm received a standard dose of 160 mg daily.

The median age of patients enrolled in the trial was 61 years, and 61% were male while 39% were female. The primary endpoint of the study was met, as 43% of patients in the dose-escalation arms were able to reach a third cycle of therapy compared with 24% of those in the standard-dose arm (P = .0281).²

Notably, OS was improved by 3 months in patients who received the dose escalation regimen at 9 months versus 5.9 months with the standard dose (P = .0943). However, the PFS benefit was not statistically different, noted Imanirad.

IMblaze370

Although TAS-102 (trifluridine/tipiracil; Lonsurf) and regorafenib both hold indications in the third-line refractory setting, emerging data suggest that regorafenib may lead to better responses in patients with a preserved performance status of 0 or 1 and should be considered as such, concluded Imanirad.In this 3-arm trial, 363 patients with refractory MSS/microsatellite instability-low (MSI-L) metastatic CRC were randomized 2:1:1 to receive the combination of atezolizumab (Tecentriq) and cobimetinib (Cotellic), atezolizumab monotherapy, or regorafenib monotherapy. The trial was launched based on phase Ib data demonstrating encouraging tolerability and efficacy, said Imanirad. Moreover, the combination of anti—PD-L1 and MEK inhibition was thought to enable better immune recognition and greater antitumor activity compared with either agent alone.

The primary endpoint of the study was OS among the ITT population, with secondary endpoints of investigator-assessed PFS, ORR, and duration of response. The median age of patients was 58 years, and 26% of patients had received >3 prior lines of therapy.

The majority of patients were MSI-L, although 3 patients with MSI-H tumors were later identified in the immunotherapy doublet and monotherapy arms, added Imanirad. PD-L1 status was relatively well balanced among the 3 treatment arms, with positivity rates of 43%, 39%, and 34% in the immunotherapy doublet arm, immunotherapy monotherapy arm, and regorafenib arm, respectively. The respective PD-L1—negative rates were 46%, 47%, and 44%.

In terms of median OS, the combination of atezolizumab and cobimetinib was superior to that of regorafenib, at 8.9 months and 8.5 months, respectively (HR, 1.00; 95% CI, 0.73-1.38; P = .9871).³ The median OS with single-agent atezolizumab was 7.1 months. However, this was not determined to be statistically significant. Additionally, the 12-month OS rate was observed to be fairly similar in patients who had received the immunotherapy doublet compared with those who received the multikinase inhibitor, said Imanirad.

PFS was worse with the combination (1.9 months) than that of regorafenib (2.0 months) regardless of whether atezolizumab was administered in combination or as monotherapy (1.9 months), added Imanirad. The rates of objective response were similar, he added. Although the ORR was slightly higher in the immunotherapy doublet arm, it was likely driven by patients with MSI-H tumors.

Regarding safety, treatment-related grade 3/4 AEs were reported in 45% of patients in the immunotherapy doublet arm, 10% of patients in the immunotherapy monotherapy arm, and 49% of patients in the regorafenib arm.

“It seems like anti—PD-L1 plus MEK inhibition might not be sufficient to elicit an adequate response in refractory colon cancer,” concluded Imanirad.

References

1. Chen EX, Jonker DJ, Kennecke HF, et al. CCTG CO.26 trial: a phase II randomized study of durvalumab (D) plus tremelimumab (T) and best supportive care (BSC) versus BSC alone in patients (pts) with advanced refractory colorectal carcinoma (rCRC). J Clin Oncol. 2019;37(suppl 4; abstr 481). doi: 10.1200/JCO.2019.37.4_suppl.481.
2. Bekaii-Saab TS, Ou F-S, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study. J Clin Oncol. 2018;36(suppl 4; abstr 611). doi: 10.1200/JCO.2018.36.4_suppl.611.
3. Bendell J, Ciardiello F, Tabernero J, et al. Efficacy and safety results from IMblaze370, a randomised phase III study comparing atezolizumab plus cobimetinib and atezolizumab monotherapy vs. regorafenib in chemotherapy-refractory metastatic colorectal cancer. Ann Oncol. 2018;29(suppl 5; abstr LBA-004). doi: 10.1093/annonc/mdy208.003.