Patients who took an immunotherapy-based drug regimen had longer life expectancy than those given chemotherapy, researchers say.
Patients with previously treated metastatic colorectal cancer who took a combination of zanzalintinib and atezolizumab had better overall survival than patients who took chemotherapy, researchers say.
The international researchers compared the efficacy of a combination of zanzalintinib – a multitargeted tyrosine-kinase inhibitor that blocks proteins involved in cell growth – plus the immunotherapy drug atezolizumab with the efficacy of the oral multi-kinase inhibitor regorafenib.
The Lancet study included 900 adults with metastatic adenocarcinoma of the colon or rectum who were randomly assigned to receive oral zanzalintinib (100mg daily) plus intravenous atezolizumab (1200mg every three weeks), or oral regorafenib (160mg daily on days one to 21 of each 28-day cycle).
All the patients had previously received standard of care therapy and did not have mismatch repair deficient (dMMR) – also referred to as microsatellite instability-high (MSI-H) – tumours.
After 18 months, patients in the zanzalintinib-atezolizumab group “showed a significant overall survival benefit”, with a median survival of 10.9 months compared with 9.4 months in the intention-to-treat group.
The international researchers said the STELLAR-303 study was the first phase 3 trial to show a significant improvement in overall survival with an immunotherapy-based regimen – zanzalintinib and atezolizumab – in patients with relapsed or refractory metastatic colorectal cancer that was not dMMR.
“This combination represents a chemotherapy-free treatment option with a novel mechanism of action for heavily pretreated patients in need of improved therapies,” they said in The Lancet.
The researchers said adverse events were consistent with known class effects and no new safety signals emerged. The most common adverse events were diarrhoea, hypertension and fatigue, which were more frequent with zanzalintinib-atezolizumab than with regorafenib, they said.
Adverse events led to 18% of the zanzalintinib–atezolizumab group discontinuing treatment, compared with 15% of participants taking regorafenib.
Professor Peter Gibbs, medical oncologist and laboratory head at The Walter and Eliza Hall Institute of Medical Research, said it was an important study because it was the first study of immunotherapy to show a survival benefit in proficient mismatch repair (pMMR) colorectal cancer – which made up most cases.
“It’s a landmark study interms of showing a survival benefit in that subset,” he told Oncology Republic.
“The limitation is that the difference isn’t that big. It’s about 1.5 months median survival gain, which is pretty modest, and there are some potential significant side effects associated with the treatment,” said Professor Gibbs, who was not involved in the research.
“It’s not really a game changer, but it’s an important step, hopefully, towards more effective immune-based strategies for the pMMR colorectal cancer.”
Professor Gibbs said patients with dMMR colorectal cancer made up about 4% of colorectal cancer cases.
“Those patients do quite well with immunotherapy. But to date, the pMMR, the other 96%, immunotherapy trials have been unsuccessful,” he said.
Professor Gibbs said the challenge was to determine which subset of patients in the study benefitted from the combination therapy.
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“Is there a biomarker that we can find that will define a subset that do benefit more?
“Presumably there’s patients that benefit four, five, six months, but if you treat everyone, it averages out at one and a half [months].
“If we can work out the minority population that is very sensitive, then it’s more of an advance.”
Professor Gibbs said a few other drugs had shown similar effects on overall survival in patients after standard chemotherapy, with an increased survival ranging from 1.5 to three months.
This study was “adding to a number of other options in that patient group”, he said.
Professor Gibbs said similar combinations of immunotherapy plus a signal transduction inhibitor – which makes the tumour more sensitive to immunotherapy – were commonly used across liver cancer and other tumour types.
“This [study] has been more successful than previous efforts, which have been a bust,” he said.
Professor Gibbs noted that this study had preliminary data and was “not the end of the story”.
“We’ve just seen early data at this point, so we need to see the formal, longer-term outcomes and publications, and that might give us a bit more encouragement,” he said.
