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CHICAGO -- Adding atezolizumab (Tecentriq) to cabozantinib (Cabometyx) for patients with metastatic renal cell carcinoma (RCC) after progression on an immune checkpoint inhibitor failed to improve clinical outcomes and led to increased toxicity, the phase III randomized CONTACT-03 trial showed.

Among over 500 patients at a median follow-up of 15.2 months, 65% of those receiving atezolizumab-cabozantinib and 64% of those receiving cabozantinib alone had disease progression or died, reported Toni K. Choueiri, MD, of the Dana-Farber Cancer Institute in Boston, during a session of the American Society of Clinical Oncology annual meeting.

Median progression-free survival was 10.6 months and 10.8 months, respectively (HR 1.03, 95% CI 0.83-1.28, P=0.78), according to findings from the study, which were published simultaneously in .

There was also no significant difference in overall survival (OS) between the two groups. Median OS was 25.7 months with atezolizumab-cabozantinib, and was not evaluable with cabozantinib (HR 0.94, 95% CI 0.70-1.27, P=0.69).

"This is a negative study, but this is an important question," Choueiri said. "These data ... highlight the importance of randomized prospective assessment of rechallenge with checkpoint inhibitors in RCC, and potentially in other tumor types."

Choueiri and his colleagues also tried to identify a subgroup that could benefit from the combination and found there were none. Furthermore, response rates were similar between the two groups, as were median time to response and duration of response.

Choueiri also noted that increased toxicity was observed with the combination. More than half (55.3%) of patients in the combination arm had a grade 3 or 4 treatment-related adverse event (TRAE) compared with 47.3% of patients in the cabozantinib-only arm, and serious TRAEs were twice as frequent with the combination (24% vs 11.7%).

Adverse events leading to death occurred in 6% of patients in the atezolizumab-cabozantinib group and 4% in the cabozantinib group. There were three deaths due to TRAEs in the combination arm and none in the cabozantinib arm.

In describing the rationale behind the study, Choueiri said that the introduction of immune checkpoint inhibitors as first-line therapy across cancer types has led to questions about optimal second-line therapy. In the case of metastatic RCC, prospective evidence supports the use of VEGF tyrosine kinase inhibitors -- including cabozantinib -- in patients previously treated with immune checkpoint inhibitors.

However, "we are seeing an emerging practice in metastatic RCC, and I would argue in other tumors, which is the rechallenge of PD-L1 or PD-1 inhibitors after initial progression on the same class of agents," Choueiri noted. This is happening, he and his team said, despite the absence of sufficient clinical trial evidence.

In a , Kathryn Beckermann, MD, PhD, and Brian Rini, MD, both of Vanderbilt Ingram Cancer Center in Nashville, Tennessee, pointed out that "there are no wider data from other cancers to support sequenced immunotherapy."

"Therefore, this rechallenge approach, which was being increasingly adopted in clinical practice, should be avoided until and unless positive data are available," they wrote. "A deeper understanding of immunotherapy resistance mechanisms is needed to design rational trials in this setting."

was a multicenter open-label trial conducted across 135 study sites in 15 countries in Asia, Europe, North America, and South America from July 2020 to December 2021.

Choueiri and team included 522 patients with locally advanced or metastatic RCC whose disease had progressed with immune checkpoint inhibitors. They were randomized 1:1 to receive atezolizumab 1,200 mg intravenously every 3 weeks plus cabozantinib 60 mg orally once daily or cabozantinib alone.

Patient characteristics were well-balanced between the arms. Median age was 62-63, and more than three-quarters of patients in each arm were white men.

The authors noted that they included patients with non-clear-cell histology, as well as patients with previous PD-1/L1 treatment in the adjuvant setting, which was a limitation to their study.