Previewing Advances in the HCC Paradigm Through Insights From the 2021 Gastrointestinal Cancers Symposium

What were the most clinically impactful abstracts in HCC presented at the 2021 Gastrointestinal Cancers Symposium?

ASCO GI was quite a successful and intriguing meeting this year. Its virtual nature is fairly novel, and I’d like to congratulate ASCO, the American Gastroenterological Association, the American Society for Radiation Oncology, and the Society of Surgical Oncology. They did an amazing job of bringing the meeting to life and placing us all in the same room; it was almost like being there in person. No doubt, it missed the close-contact interactions that remain valuable to help move the field forward, but, in sum, the Symposium did achieve its goals and addressed all that is upcoming in GI malignancies.

The 2021 Gastrointestinal Cancers Symposium offered great news for patients with cholangiocarcinoma. Final results from the [phase 3] ClarIDHy study (ClinicalTrials.gov Identifier:  NCT02989857) evaluating ivosidenib against placebo in patients with advanced IDH1-mutant cholangiocarcinoma included updated survival data.¹ The rank-preserving structural failure time helped demonstrate a continued improved survival of 10.3 months for ivosidenib and 5.1 months for placebo, with a hazard ratio of 0.49. We are all excited; we all have hands-on experience with ivosidenib, and we very much look forward to seeing it approved by the US Food and Drug Administration and by other agencies for our patients with IDH1-mutated cholangiocarcinoma.
 
A second abstract of critical importance featured the results of a [phase 3 study of] infigratinib, a fibroblast growth factor receptor (FGFR)-selective tyrosine kinase inhibitor, in patients with advanced cholangiocarcinoma with an FGFR2 fusion or other FGFR genetic alterations (ClinicalTrials.gov Identifier: NCT03773302). As part of this effort, we were able to further assess the outcomes of patients and adverse events in this study. We now have a finalized set of data, showing through central review an objective response rate of 23.1% that went up to 34.0% in the second-line setting, with a median progression-free survival of 7.3 months.²
 
The topic of HCC was also covered robustly at the meeting, with further updated data of clinical importance. It has been an amazing couple of years, with so many HCC trials reported. Thankfully, most are positive. Some looked into novel tyrosine kinase inhibitors, others looked into checkpoint inhibitors, and probably the most novel was the combination of the checkpoint inhibitors plus the different tyrosine kinase inhibitors or anti-vascular endothelial growth factor (VEGF) agents.
 
To start in HCC, I would like to spend time discussing the combination of 2 checkpoint inhibitors, nivolumab plus ipilimumab, studied in the CheckMate 040 study (ClinicalTrials.gov Identifier: NCT01658878) across 3 arms.³ In Arm A, nivolumab was administered at 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for 4 doses. This combination, now known as NIVO 1 + IPI 3, showed an impressive median overall survival (OS) of 22.2 months.³ This combination came with added toxicity, with the “proportion of grade 3 or 4 treatment-related adverse events [appearing] to be higher [with] the ipi/nivo combination” compared with durvalumab plus tremelimumab, as previously reported.³

Findings from a meta-analysis⁴ that compared the efficacy of systemic therapies in advanced HCC suggested that atezolizumab-bevacizumab might be superior to lenvatinib monotherapy in the frontline setting, based on better OS benefit. However, lenvatinib was found to afford a better overall response rate (ORR) than atezolizumab-bevacizumab. The analysis further suggested that cabozantinib should be given preference in the second-line setting. How do these findings complicate or validate existing sequencing strategies in HCC?

The findings of the meta-analysis comparing the efficacy of systemic therapy in advanced HCC were intriguing. The data again suggested atezolizumab plus bevacizumab have a superior OS benefit compared with lenvatinib monotherapy in the frontline setting but showed a better ORR with lenvatinib than with atezolizumab plus bevacizumab. Not surprisingly, the analysis also suggested that cabozantinib is the preferred tyrosine kinase inhibitor in the second-line setting.⁴
 
How these findings complicate or validate existing and potential sequencing strategies in HCC is yet to be determined, but it is key that one does not look at lenvatinib the same as one looks at sorafenib. Sorafenib and lenvatinib are different, and a way better progression-free survival and response rate are seen with lenvatinib.
 
We were also happy to see an update on pembrolizumab monotherapy in HCC from the phase 2 KEYNOTE-224 study (ClinicalTrials.gov Identifier: NCT02702414), which showed an OS benefit in patients with advanced HCC who had not received prior systemic therapy.⁵ A median duration of response was not reached in this update, while best ORR included a 60% partial response rate and 41% stable disease rate. Progression-free survival at 18 months was 60%.
 
By all means, this does not really undermine the fact that studies that compared pembrolizumab against placebo were negative but, nonetheless, it is highly suggestive and supportive of the value of pembrolizumab as a single agent in regard to the treatment of HCC and supports the continued and further evaluation of pembrolizumab-based regimens in the frontline treatment of HC.

Data from the phase 1b DEDUCTIVE trial⁶ showed that the VEGF-receptor inhibitor tivozanib was well tolerated when combined with durvalumab. Interest in combined programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) and VEGF blockade in HCC has risen amid findings of the IMbrave150 trial, which validated the efficacy of this approach via atezolizumab and bevacizumab. Mechanistically, why is dual VEGF and PD-1/PD-L1 obstruction an appealing strategy in HCC, and how is this approach expected to affect drug development efforts in the near future in this disease setting?

This anti-VEGF plus the anti-PD-1/PD-L1 activity of tivozanib in combination with durvalumab is similar to what we have seen with atezolizumab plus bevacizumab. It’s nice to see that there was also activity in the DEDUCTIVE study (ClinicalTrials.gov Identifier: NCT03970616), which evaluated tivozanib, another anti-VEGF agent, in combination with durvalumab. This study provides an early look at the outcome with that combination and shows clearly that doublet therapy was well tolerated. The phase 2 portion of the study continues to have further patients.
 
Of course, other combination therapies are looked at in HCC, and one should not look at them as being all the same. Other combinations include tyrosine kinase inhibitors plus anti-PD-1, and the combination of the checkpoint inhibitors such as anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) plus anti-PD-1 or anti-PD-L1. This was illustrated in updated data presented at the meeting on the combination of nivolumab plus ipilimumab.³ Second-line nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg for 4 doses) continued to demonstrate a clinically meaningful response and long-term survival benefit with a reduced, but still present, concern of toxicity secondary to the repeated dosing of anti-CTLA-4. Of course, we all look forward to the HIMALAYA study (ClinicalTrials.gov Identifier:  NCT03298451), which is evaluating durvalumab plus 1 dose of the anti-CTLA-4 agent tremelimumab.
 
Who will respond to what remains a critical question, which one would anticipate would be best answered not based on etiology or ethnicity but on a detailed understanding of the tumor immune microenvironment.

What insights did ASCO GI offer for HCC providers concerned about care coordination amid COVID-19?

It was nice to see a great report from the United Kingdom looking into COVID-19 infection in patients with GI cancer who are receiving systemic anticancer treatment during the pandemic. The experience of the Cancer Centre at Guy’s Hospital in London is valuable and showed that the rate of COVID-19 infection in the population was relatively limited.⁷ Of course, this report needs to be placed into context with the lack of comparative data, but it did provide a certain clarity that, independent of COVID-19, patients should continue to receive the needed therapy for their GI malignancies.