Integrating Surgical, Systemic Approaches Into HCC

Vatche G. Agopian, a professor of surgery and pharmacology at the University of California, Los Angeles, presented data to support adjuvant therapy after resection or ablation of hepatocellular carcinoma (HCC) at the 20th Annual Meeting of the International Society of Gastrointestinal Oncology.

Up until recently, the only large, randomized, controlled study was the STORM study of adjuvant sorafenib. Unsurprisingly, Dr. Agopian stated, there was not much difference in recurrence-free survival (RFS) from investigative sorafenib (versus placebo).

Additionally, there was the IMbrave-050 study of atezolizumab plus bevacizumab versus active surveillance. Criteria for high risk of HCC recurrence in the resection arm was tumor >5 cm, at least 4 tumors, and either vascular invasion or poor tumor differentiation. After a median follow-up of 17.4 months, the study met its RFS end point with a hazard ratio of 0.72 (95% CI, 0.56-0.93) favoring the atezolizumab-plus-bevacizumab arm. However, just a few months later that benefit diminishes, and RFS starts to level out with active surveillance.

This study begs a few questions, Dr. Agopian says, one of which is “Are we just delaying an inevitable recurrence or are we improving overall survival?”

Then, he transitioned to providing an overview of the neoadjuvant systemic therapy options for HCC. This strategy is thought to improve surgical outcomes because the micro-metastases are treated earlier, the tumor being there allows the therapy to act as an in vivo test, and the presence of the tumor helps prime the immune system to recognize tumor neoantigens. However, with the neoadjuvant approach, there is no histologic confirmation, and the primary curative therapy is deferred with a “real and finite risk” of drop out from either treatment toxicity or tumor progression.

Where are the data to support neoadjuvant systemic therapy in a prospective manner? A phase 1b study from Johns Hopkins looked at neoadjuvant cabozantinib plus nivolumab in patients who were deemed surgically unresectable. After treatment and then reassessment at 8 to 10 weeks, 13 of the total 15 patients were converted to resection candidates and 12 underwent resection successfully. Five of these patients had a major or complete pathologic response.

Several studies have looked at a perioperative approach, including a phase 2 trial of perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable HCC. Of the 27 patients, no difference in progression-free survival was noted between the groups, and the patients in the combination arm had slightly worse adverse events.

Another phase 2 study assessed neoadjuvant cemiplimab for resectable disease. Twenty percent of patients had a major pathologic response to therapy.

“None of these studies have given any evidence that we are improving rates of recurrence or overall survival,” he stated. “Hopefully, these questions will be answered with the numerous ongoing neoadjuvant studies.”

Finally, he concluded with a discussion on immunotherapy in the transplant-eligible, which is controversial because while tumor growth decreases, the potential for graft rejection increases. Different immune checkpoint inhibitors are being assessed in case studies and small trials, with different duration or cycles, time between last therapy dose and transplantation, assessment of allograft outcome, and outcomes assessments. “This a hot area of investigation,” he said, adding that “at this point, there [are] not enough data to definitively make any recommendation for post-transplantation immunotherapy use.”

In summary, he stated that utilization of immunotherapy in the adjuvant setting following resection delays recurrence, but the impact on overall survival and cure rates remains unclear. Additionally, neoadjuvant and perioperative immunotherapy prior to resection is safe and may allow for downstaging to resection while providing pathologic response rates around 20% to 30%, but the impact on recurrence rates or overall survival also remains unclear. Lastly, pretransplant immunotherapy appears safe, but ongoing trials are needed to assess the risks and benefits.