Combination Immunotherapy in Low Tumor Burden HCC

Richard Kim, MD

Professor of Oncology

University of South Florida Health Morsani College of Medicine Service Chief of Medical Gastrointestinal Oncology

Senior Member

Gastrointestinal Oncology Department

Moffitt Cancer Center

Tampa, FL

At a live virtual event Richard Kim, MD, discussed treating patients with hepatocellular carcinoma and how the treatment approach to this disease has changed. Kim recaps the current therapies available for these patients and how approaches to treatment may differ depending on the patient’s characteristics. Further, he looks at the results of the study that showed the potential for tremelimumab (Imjudo) and durvalumab (Imfinzi) as a combination therapy in this patient population.

UNDERSTANDING HCC

Broadly speaking, the one thing we have to understand is that treatment for patients with HCC [hepatocellular carcinoma] requires a multitherapy approach. Depending on the stage of disease, with the more common stage [we see recorded by] the Barcelona Clinic Liver Cancer [BCLC] staging system, [patients who are] early BCLC stage A are candidates for surgery or transplant.¹

The patients we see in our medical oncology clinics are probably BCLC stage B or C. Patients with BCLC stage B disease have intermediate HCC, where they have a multifocal disease in the liver without any evidence of vascular invasion, nodes, or extrahepatic disease.² In the past, the mode of treatment was [most commonly] locoregional therapies, Y90, or chemoembolization. [For patients with] BCLC stage C, more advanced disease, we use systemic therapies now, but in the past, you could argue that we did some locoregional therapy because we did not have any good treatments available.²

Well, it’s different in 2023, and I think oncologists have to take the lead now, because there are so many drugs out there that are useful in this setting. [With the new treatments available], the key point now is that the patient needs to be seen in a tertiary center where we can offer all these treatment options.

CURRENT THERAPY OPTIONS IN HCC

If you look at the systemic therapy options [to treat patients with] HCC, some are FDA approved [and in the National Comprehensive Cancer Network guidelines, whereas] some are not available in the US.³ One that is available and we use is atezolizumab [Tecentriq] plus bevacizumab [Avastin], [which is approved, whereas] nivolumab [Opdivo] and ipilimumab [Yervoy] is conditionally approved.³

Nivolumab as a single agent [for patients with HCC] has been taken off the market because it was negative in a phase 3 study in the first-line setting. Pembrolizumab [Keytruda] is still available in the refractory setting, but more recently tremelimumab and durvalumab was approved in the first-line setting.⁴ [Other drugs that have] been studied but [are] not FDA approved [include] atezolizumab with other PD-1 inhibitors, which were mostly studied in Asia with some positive results…but once again, not available here in the US.³

HIMALAYA TRIAL RESULTS

[Prior to the] 3-year follow up, if you looked at median overall survival [OS] in the HIMALAYA study [NCT03298451], it was a little less than a 3-month difference favoring the tremelimumab and durvalumab [STRIDE] regimen at 16 months vs 13.8 months with sorafenib [Nexavar], which was how the drug was approved.5 Now, if you look at 36 months of OS, [approximately] 30% of patients on STRIDE will get there compared with 20% in the sorafenib arm.

[Approximately] one-third of the patients who got the STRIDE regimen were still alive at 3 years, which [was not possible] a couple years ago; we had never seen this kind of OS number.⁵ Recently, [researchers] presented a 4-year OS, and [although] the number of patients [is decreasing]…at 4 years, [approximately] one-quarter of the patients were still alive on [the STRIDE regimen], at 25.2% vs 15.1% [for those patients on sorafenib]. However, we have to look at OS in terms of [median months], which was 16.4 [95% CI, 14.2-19.6] vs 13.8 [95% CI, 12.3-16.1] months, which is really just a 2- or 3-month difference [HR, 0.78; 95% CI, 0.67-0.92; P = .004].⁵

One of the interesting points about HIMALAYA is that if you look at the durvalumab-[alone] arm, it met [the end point]. If you look at it compared with durvalumab plus tremelimumab, [the combination] did better, but durvalumab alone wasn’t far off.⁵ Comparing sorafenib vs durvalumab [at the 4-year OS mark, approximately] 20% of patients were still alive with durvalumab. Then if you look at OS at 36 months, [approximately] one-quarter of the patients were alive with durvalumab alone.⁵ The point is that the durvalumab and tremelimumab combination is good, but even single-agent durvalumab would have some good efficacy [in this patient population]. Once again, I want to point out that durvalumab alone is not approved by the FDA [for patients with HCC] in the first-line setting, but it is something to think about in patients with a poor ECOG performance status or [those who] are not eligible for doublets. This is just something to think about, because it seems to do better than the tyrosine kinase inhibitor.

DETERMINING A PATIENT’S RESPONSE

The overall response rate was [approximately] 20% when adding the complete responses and partial responses on the STRIDE regimen.5 However, the question is: With any immunotherapy, which patients are doing better? How do I know [whether] the patient will do well with the immunotherapy? At this moment, unfortunately, we do not have a biomarker [to predict responses with]. I wish I could tell you there was a biomarker, like their PD-1 status, but PD-1 is useless in HCC, so don’t test for it.

There is no biomarker that’s going to tell [whether] my patient is going to do well with this regimen; however, you could look at the response rate for the patient with a long-term survival. For the patients [who] did well at 4 years, what [researchers] saw was that they had some form of response to the therapy [early].⁵ So, when I see a patient, I tell them that the first 2 scans are very important, because if you see response in the first few scans, [they] will most likely do well, [regardless of response criteria].

IMMUNOTHERAPY TOXICIITIES

One of the things we see [with this treatment] is immune-mediated adverse events [imAEs], and there are a lot of imAEs that we see in our practice—not commonly, but we see them…. In this study, they did a post hoc analysis looking at which patients had imAEs and compared [their OS with] the patients who did not have imAEs....⁶

[These] data show that patients who had imAEs...their median OS was 23.2 months [95% CI, 19.1-32.4] compared with [patients not on immune therapy] and [who] didn’t have imAEs, which was a median OS of 14 months [95% CI, 11.6-17.9].⁶ Once again, I want to make the point that this [study] was not powered to show this kind of benefit, as it was just a post hoc analysis, but they are interesting findings.... [That] means if the patient gets an autoimmune problem with this kind of therapy, as long as [we work in] conjunction with our colleagues, we should try to push them through [as the patients are] seeing benefits.

In the past, an autoimmune disease was the contra-indication, but now I will say that we’re pushing boundaries more and more. [For example], I’ve given a patient immunotherapy who had ulcerative colitis, I’ve given immunotherapy [to a patient] with Crohn disease, [and] I have even given [immunotherapy to] a patient with primary biliary cirrhosis. Clearly, we’re pushing more and more in this area, understanding that we know how to manage the AEs if they occur. Again, this has to be done in conjunction with other specialists, and at Moffitt Cancer Center, we fortunately [have those resources]. I’ve been able to push the boundary, and some of the patients had a very good response [to treatment], especially a patient with ulcerative colitis with HCC [who is] responding beautifully with combination immunotherapy.

Those things can happen, and the clear point is that imAEs [are expected], and we get to control it. If you think the benefit will outweigh the risk, then you should continue [treatment for the] patient with some form of steroids, if needed. The most common AEs in the HIMALAYA study were mostly grade 1 and 2 thyroid issues. Durvalumab as a single agent had very few imAEs, but if you add tremelimumab...your rate of imAEs does go up.⁷ Once again, these were mostly grade 1 and 2 AEs, with some grade 3 and 4 toxicities. If you look at the overall incidence of when [these AEs] occur, they usually occur within the first 2 to 4 months [of treatment].

I think a lot of us have good experience [handling these AEs] in the community setting, because [community oncologists] use immunotherapy for other [patients with] cancer, not just those with HCC, so [there is familiarity in] using it. However, this is no exception, so we need to be aware of these imAEs, treat them accordingly, and weigh the risk and benefit. If you look at the STRIDE regimen vs durvalumab alone and sorafenib alone...as you would expect, durvalumab alone was the best tolerated, and the worst tolerated [was] sorafenib.⁷

We’ve given sorafenib before, and sometimes it’s not easy to give, [but durvalumab] in the STRIDE regimen had a discontinuation rate of 8.2% [Table⁷]. However, the key [factor] we need to be aware of is that, in this study, [approximately] 20% of the patients got some form of steroids because of their imAEs.⁷

_REFERENCES

_{1. Liver cancer stages. National Cancer Institute. Updated May 18, 2022. Accessed November 22, 2023. https://tinyurl.com/y7uzpdrh}

_{2. Koh B, Tan DJH, Lim WH, et al. Trial watch: immunotherapeutic strategies on the horizon for hepatocellular carcinoma. Oncoimmunology. 2023;12(1):2214478. doi:10.1080/2162402X.2023.2214478}

_{3. Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18(8):525-543. doi:10.1038/s41575-021-00438-0}

_{4. FDA approves tremelimumab in combination with durvalumab and platinum-based chemotherapy for metastatic non-small cell lung cancer. FDA. November 18, 2022. Accessed November 22, 2023. https://tinyurl.com/4hyy5ryp}

_{5. Sangro B, Chan S, Kelley R, et al. Four-year overall survival update from the phase 3 HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Annl Oncol. 2023;34(1):S1688. doi:10.1016/j. annonc.2023.04.487}

_{6. Lau G, Cheng AL, Sangro B, et al. Outcomes by occurrence of immune-mediated adverse events (imAEs) with tremelimumab (T) plus durvalumab (D) in the phase 3 HIMALAYA study in unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2023;41(suppl 16):4004. doi:10.1200/JCO.2023.41.16_suppl.4004}

_{7. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8). doi:10.1056/EVIDoa2100070}