First-Line IO Yields Long Survival in MSI-H/dMMR Colon Cancer

This article is a collaboration between MedPage Today and:

SAN FRANCISCO -- The scientific program of the Gastrointestinal Cancers Symposium included more than 800 abstracts over the three days of the meeting. Three of the top presentations from the meeting involving immunotherapy (IO) in gastrointestinal cancers are summarized below.

Durable Responses With First-Line IO in MSI-H/dMMR Colorectal Cancer

Combined anti-PD-1/CTLA-4 immunotherapy yielded long-lasting responses and impressive survival rates for untreated patients with metastatic colorectal cancer and high microsatellite instability (MSI-H) or mismatch repair-deficiency (dMMR), updated results of the phase II CheckMate 142 trial indicated.

Among the 45 patients in the study treated with nivolumab (Opdivo) and low-dose ipilimumab (Yervoy), neither median progression-free survival (PFS) nor overall survival (OS) was reached at a median of 20 months follow-up, Heinz-Josef Lenz, MD, of the University of Southern California Norris Comprehensive Cancer Center in Los Angeles, told the audience here.

At 15 months, the PFS and OS rates were 75% and 84%, respectively.

The combination was highly active, with 18% of patients achieving a complete response (CR) on blinded independent central review and 40% having partial responses.

"Nivolumab and low-dose ipilimumab demonstrate clinically meaningful and durable benefits and may present an option for first-line treatment for MSI colorectal cancer," said Lenz.

In CheckMate 142, patients with metastatic MSI-H/dMMR colorectal cancer were treated intravenously with nivolumab (3 mg/kg every 2 weeks) plus low-dose ipilimumab (1 mg/kg every 6 weeks) until disease progression or unacceptable toxicity. In all, 58% of patients responded and 22% had stable disease, for a disease control rate of 78%, and 84% had some degree of tumor shrinkage to their target lesion.

Grade 3/4 treatment-related adverse events (AEs) occurred in 20% of patients, serious grade 3/4 AEs occurred in 11%, and 11% stopped therapy due to a treatment-related AE.

Patients were a median age of 66, and most (62%) had been diagnosed with earlier-stage disease before eventually developing metastatic lesions. Subgroup analyses -- right- and left-sided tumors, KRAS/BRAF mutation status, and others -- showed that all subgroups derived similar benefit from treatment.

QOL Maintained With New First-Line Standard in HCC

Along with improving survival, a quality of life (QOL) analysis from the IMbrave150 trial showed that unresectable hepatocellular carcinoma (HCC) patients on atezolizumab (Tecentriq) plus bevacizumab (Avastin) had significantly improved patient-reported outcomes compared to those treated with sorafenib (Nexavar), the current standard of care.

"The assessed quality of life, role functioning, physical functioning, and key symptoms all were delayed, occurring less often in favor of the combo versus sorafenib," said Peter Galle, MD, PhD, of the University Medical Center Mainz in Germany.

Indeed, deterioration across all these measures were significantly delayed in the atezolizumab-bevacizumab arm compared with the sorafenib arm, respectively:

• QOL: 11.2 vs 3.6 months (HR 0.63, 95% CI 0.46-0.85)
• Role functioning: 9.1 vs 3.6 months (HR 0.62, 95% CI 0.46-0.84)
• Physical functioning: 13.1 vs 4.9 (HR 0.53, 95% CI 0.39-0.73)

Aside from jaundice (HR 0.76, 95% CI 0.55-1.07), all key symptoms on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire were significantly improved in the atezolizumab-bevacizumab arm:

• Appetite loss: HR 0.57 (95% CI 0.40-0.81)
• Diarrhea: HR 0.23 (95% CI 0.16-0.34)
• Fatigue: HR 0.61 (95% CI 0.46-0.81)
• Pain: HR 0.46 (95% CI 0.34-0.62)

On EORTC QLQ-HCC18 -- an HCC-specific questionnaire -- improvements in fatigue and pain were also seen in favor of the combination.

"These patient-reported outcomes -- the patients' voice -- further support the positive benefit-risk profile of atezolizumab and bevacizumab versus sorafenib, and in a nice way complement the efficacy data in these patients with unresectable HCC who have not received prior systemic therapy," said Galle.

The primary analysis of IMbrave150, reported in the fall, showed that the two-drug combination improved PFS and OS "at a level not seen before compared to sorafenib," said Galle.

Median OS was not reached with atezolizumab-bevacizumab versus 13.2 months with sorafenib (HR 0.58, 95% CI 0.42-0.79, P=0.0006). Median PFS was 6.8 months versus 4.3 months, respectively (HR 0.69, 95% CI 0.47-0.76, P<0.0001).

On Monday, manufacturer Roche announced plans to seek approval for the combination as a new frontline therapy for unresectable HCC and many experts are saying it will become the new standard of care for such patients.

IMbrave150 enrolled 501 patients with locally advanced or metastatic HCC and randomized them 1:1 to atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) delivered intravenously every three weeks or twice daily oral sorafenib (400 mg).

For the PROs analysis, patients completed the questionnaires prior to starting treatment, then every three weeks during treatment, and every three months after discontinuation until progression. Completion rates remained at 92% or above during treatment. Deterioration in QOL, role functioning, and physical functioning was defined as a 10-point drop on the EORTC QLQ-C30 instrument, a level that patients have described as being clinically meaningful.

Cabozantinib Immunotherapy Combinations Active in HCC

In a similar setting, treatment with cabozantinib (Cabometyx) plus immunotherapy yielded promising antitumor activity as a first- or second-line treatment for patients with advanced HCC, results of the phase I/II CheckMate 040 study showed.

Among 35 patients assigned to the multikinase inhibitor cabozantinib plus both nivolumab and ipilimumab, blinded independent central review found that 31% responded to the triplet, including CRs in 6%, reported Thomas Yau, MD, of the University of Hong Kong.

Additionally, 46% of patients achieved stable disease. With a follow-up of 19.4 months, median OS was not reached, and 70% lived a minimum of 15 months.

Investigators also assessed the doublet of cabozantinib plus nivolumab alone, which appeared less active. In the 36 patients on this regimen, 14% responded (including one CR), and 56% had stable disease, according to central review. Median OS was 21.5 months, and 64% of patients were alive at 15 months.

In each of the two arms, more than two-thirds of patients had some form of tumor shrinkage in their target lesion. Median PFS was 5.4 months with the doublet and 6.8 months with the triplet.

"Investigation with a longer duration of follow-up may be necessary to better assess the true benefit-risk ratio of both the doublet and triplet combination in patients with advanced HCC," said Yau.

In the triplet arm, 11% of patients discontinued due to treatment toxicity versus 6% with the doublet.

CheckMate 040 enrolled 71 adults with advanced HCC who were naive to sorafenib or had progressed on or were intolerant of the standard treatment. In the doublet arm, patients received cabozantinib daily at an oral dose of 40 mg and nivolumab at a dose of 240 mg intravenously every 2 weeks. In the triplet arm, patients received cabozantinib (same dose), and intravenous nivolumab (3 mg/kg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks). Median durations of therapy were 7.1 months with the doublet and 7.8 months with the triplet.

A little more than two-thirds of patients (69%) were white and one-fourth were Asian. In the doublet and triplet arms, respectively, 53% and 66% of patients had received prior sorafenib, and more patients in the triplet arm had extrahepatic spread (65.7% vs 47.2% with the doublet).