Immunotherapy or TKI: Debating the best HCC treatment options
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Thomas A. Abrams, MD, senior physician at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School, spoke with Healio about treatment options for patients with hepatocellular carcinoma. He discusses first-line treatment, guidance on aspirin use and important, recent FDA approvals.
Healio: What is the first line treatment for HCC?
Abrams: The first line treatment for advanced HCC has evolved fairly rapidly, and there are now several excellent choices. As the audience I am sure is aware, sorafenib (Nexavar, Bayer and Onyx Pharmaceuticals) has been around for more than a decade based off of the data from the SHARP trial, and then we had nothing new for a long time until lenvatinib (Lenvima, Eisai). Lenvatinib is also a multi-targeted tyrosine kinase inhibitor, which was approved based on data from the REFLECT trial. REFLECT was a Phase III trial that randomized patients between lenvatinib and sorafenib. It was criticized for having OS non-inferiority as its primary endpoint, which was met. More interestingly, it demonstrated significantly better progression-free survival and response rate than sorafenib, and had a different side effect profile than sorafenib with less HFSR but greater hypertension. This year, very exciting data were presented looking at an IO combination of atezolizumab (Tecentriq, Genentech/Roche) and bevacizumab (Avastin, Genentech). The combo had a very high response rate and excellent overall survival, which was significantly better than sorafenib. This combination is not yet FDA approved, but is likely to be approved sometime this year.
FDA approvals have been understandably slowed because of COVID-19, but because both atezolizumab and bevacizumab are approved for other uses, this combination is now being used off label as a first-line approach. At this point, it is hard to say whether we should be using atezolizumab and bevacizumab as the first line or whether we should be sticking to lenvatinib or even sorafenib for some patients.
For patients who are in good health and can withstand the rigors of a TKI, lenvatinib remains a very good first line treatment. For patients who have a slightly more fragile aspect to them, atezo-bev might be preferable.
Hanging over this discussion is COVID-19 which is really going to color a lot of treatment decisions. Maybe oral drugs become more attractive because there is no role for office-based infusions, and much of the symptom tracking can be done by phone or video.
Additionally, there are other combinations with IOs and TKIs that are in the pipeline, where trials are close to completion or have recently finished and data readouts should be happening soon. So, the first-line regimens are going to continue to evolve over the next couple of years.
Healio: What are the most important FDA approvals in recent years?
Abrams: The lenvatinib approval was very important. Any approval in HCC is a big deal because we have not had anything new for so long. The first second-line approval was regorafenib (Stivarga, Bayer) and that was major, too. Although regorafenib is very similar to sorafenib, there was a tremendous overall survival benefit compared with best supportive care.
Then cabozantinib (Cabometyx, Ipsen) was approved, which is also a TKI, but with different targets, as a second- or third-line treatment. Then you had approvals of pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol-Myers Squibb) and more recently nivolumab plus ipilimumab (Yervoy, Bristol-Myers Squibb) that is an IO-IO combination of a PD1 inhibitor and a CTA4 inhibitor.
Now we are likely to get the atezolizumab-bevacizumab approval. In the pipeline, there are combinations such as lenvatinib and pembrolizumab, durvalumab (Imfinzi, AstraZeneca) and tivozanib (Fotivda, AVEO Oncology), and atezolizumab and cabozantinib. We are on the cusp of having a tremendous number of competing regimens in different lines, and though it is bound to create confusion, it is an excellent development for patients. It will be incumbent upon oncologists to gain experience with these regimens to better guide our patients.
Guidelines are going to be really important in trying to tease out for whom certain regimens should be deployed. There will undoubtedly be growing pains over the course of months and years as new insights creep into clinical practice which answer these questions. And as I mention previously, COVID-19 will play a large role in these decisions, too.
Healio: Can aspirin reduce the risk for HCC?
Abrams: Aspirin has been shown to be a preventive for cancers of all stripes, and particularly GI cancers, for years. The benefits seem to be limited to patients who have been on aspirin for at least 10 years. But the benefits are stark with 50% reductions in colon cancers and colon polyps, and similar reductions in esophagogastric and liver cancers.
These are very striking reductions in incidence, but you have to balance that with the increased incidence of bleeding. Patients who are at risk for liver cancer likely have at least some degree of cirrhosis. So, their blood probably does not clot normally and they might also have low platelets. If they have esophageal and gastric varices from portal hypertension, they could develop catastrophic bleeding. So, are you going to want to prescribe aspirin to these patients, knowing that the benefits do not accrue for 10 years?
The reduced incidence of liver cancer with aspirin is retrospectively real, but it remains hard to prospectively place patients at risk on aspirin, given the bleeding risk. It is different when, say, it is a patient who makes a lot of colon polyps and you want to prevent colon cancer. The cost benefit ratio for aspirin in that situation is likely in the patient's favor, but it probably is not for liver cancer.
More interesting, is the discovery that drinking three to four cups of coffee a day may actually have a similarly stark effect in preventing liver cancer; 50% reductions vs. non-coffee drinkers. Coffee does not increase the incidence of GI bleeding, so maybe we should say to patients, “Hey, let’s step up the coffee intake” because that may garner a similar benefit without the risk.
Healio: Are there resistance concerns with any HCC treatments?
Abrams: Resistance is a fundamental aspect of cancer therapy, as the audience is well aware. For IO’s, T cell exhaustion is an important mechanism of resistance.
For TKIs, mutations develop within the binding pockets that cause these drugs to lose their efficacy over time. It is interesting though, regarding resistance in TKIs, that sometimes you can overcome that resistance just by administering a very similar drug. For example, if a patient did well on sorafenib and then only recently progressed after long-term disease stability, you can put them on regorafenib and they can once again achieve long-term disease stability and extend their survival.
It shows that resistance can be overcome with TKIs. I do not know that we have the same data with immunotherapy but yes, all cancer therapies are subject to the development of resistance.
Healio: What is the role of chemotherapy in HCC management?
Abrams: If you have a cancer that is really poorly differentiated, where it is hard to say if it is HCC or cholangiocarcinoma or it has aspects of both, gemcitabine and cisplatin can be used. But the truth is that in pure HCC, chemotherapy is seldom very effective.
There are data with FOLFOX out of East Asia that show it can be occasionally effective, but we have better options now. In my opinion, cytotoxic chemotherapy is an HCC treatment of last resort.
Healio: How has COVID-19 impacted your practice?
Abrams: We developed a document in our own group at Dana Farber for treatment of advanced HCC in the COVID-19 era. After considerable debate, we decided that in cases of clinical equipoise, we prefer to initiate treatment with TKIs over intravenous IO regimens for patients who are newly starting on treatment for advanced HCC. TKIs require quite a bit of follow-up, but much of it can be done remotely decreasing a patient’s risk of contracting COVID-19 in the hospital or clinic.
IOs also carry a worrisome potential for making cytokines storm more likely in patients who have contracted COVID-19.
When we crafted this document, we consulted with those on the immunotherapy vanguard who agreed this was a legitimate concern. This is not to say that we shun the use of IOs in the COVID-19 era, not at all. However, if all else is equal, we prefer TKIs for as long as COVID-19 is a major concern or until new data come to light that show our concerns are unfounded.
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