Atif Hussein, MD, discusses how the treatment of patients with hepatocellular carcinoma and cholangiocarcinoma has evolved in recent years.
Atif Hussein, MD
Treatment for patients with advanced hepatocellular carcinoma (HCC) continues to evolve with several promising combinations, according to Atif Hussein, MD, a hematologist/oncologist at Memorial Healthcare System.
For example, the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) led to a 42% reduction in the risk of progression or death in patients with unresectable HCC, according to topline findings from the phase III IMbrave150 trial, which were presented at the 2019 ESMO Asia Congress.1
Another combination is pembrolizumab (Keytruda) and lenvatinib (Lenvima), which received a breakthrough therapy designation from the FDA in July 2019 for use as frontline therapy in patients with advanced unresectable disease that is not amenable to locoregional therapy. The regulatory decision was based on updated data from the phase Ib KEYNOTE-524/Study 116 trial. An initial interim analysis showed that treatment with the regimen led to an objective response rate (ORR) of 36.7%.2
Additionally, results from a cohort of the phase I/II CheckMate-040 trial indicated that the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) led to a 31% ORR and a median duration of response (DOR) of 17 months in patients who had prior exposure to sorafenib (Nexavar).3 Based on the results of the trial, in November 2019, the FDA granted a priority review designation to a supplemental biologics license application for the combination.
In cholangiocarcinoma, novel treatments are just beginning to emerge. For example, data from the phase III ClarIDHy trial demonstrated a 63% reduction in the risk of progression or death with the IDH1 inhibitor ivosidenib (Tibsovo) versus placebo in patients with advanced IDH1-mutant disease who had progressed on prior therapy. The median PFS was 2.7 months versus 1.4 months with ivosidenib versus placebo, respectively (HR, 0.37; 95% CI, 0.25-0.54; P <.001). Despite significant crossover to ivosidenib, data also showed a trend toward improved overall survival (OS) with the agent.4
Additionally, data from the phase II FIGHT-202 trial showed that the FGFR inhibitor pemigatinib led to a 36% ORR and a median DOR of 7.5 months in a cohort of patients with FGFR2 fusions or rearrangements.5 In November 2019, the FDA granted a priority review designation to a new drug application for the agent for patients with previously treated, locally advanced or metastatic disease who harbor the FGFR2 alteration.
“A couple of years ago, this conversation would have lasted a couple of minutes, but we've come a really long way,” said Hussein. “Now, [the treatment landscape] is becoming very exciting, especially for our patients.”
In an interview during the 2019 OncLive® State of the Science Summit™ on Gastrointestinal Malignancies, Hussein discussed how the treatment of patients with HCC and cholangiocarcinoma has evolved in recent years.
OncLive: How has the management of HCC changed in recent years?
Hussein: It is really exciting to talk about HCC, which we now refer to as liver cancer. Liver cancer is becoming an epidemic in Asia and some other countries because of the incidence of hepatitis B. [In the United States], it's becoming a problem due to hepatitis C as well.
The phase III SHARP trial was a breakthrough trial that was published 10 years ago. In the trial, sorafenib improved OS in patients with inoperable HCC. [At that point], we only had a couple of chemotherapy drugs that we used out of desperation. The trial really opened the floodgates for how we manage [patients with] liver cancer. It's complicated; you’re really treating 2 diseases in 1 because you’re treating the liver cirrhosis, which is the underlying cause, as well as the cancer itself. Therefore, you need to be careful: [be aware of] what you can and can't do and include a [multidisciplinary team] in the care of these patients.
Could you discuss the potential of atezolizumab and bevacizumab in the frontline setting?
This is a really exciting combination. [In November 2019, results of the phase III IMbrave150 trial] showed that the combination of atezolizumab and bevacizumab was superior to sorafenib as frontline therapy. The trial met its coprimary end points of progression-free survival (PFS) and OS and showed that the differences between arms were not only statistically significant, but clinically significant as well.
Nivolumab and ipilimumab is another promising combination. Could you discuss the data that have been observed with that regimen?
The combination of these drugs makes a lot of sense; one of them inhibits PD-1 and the other inhibits CTLA-4. Therefore, [with this combination, we can] remove 2 brakes that the cancer puts on the immune system. [In terms of toxicity], the regimen is very manageable, and we have become very smart about the doses we use. Ipilimumab is given for 4 doses, and nivolumab is continued. This is really an [effective] combination in select patients with good performance status.
Pembrolizumab did not significantly improve PFS or OS versus best supportive care in the phase III KEYNOTE-240 trial. What do these data mean for its use in the field?
Pembrolizumab was approved based on a small phase I/II trial. The response rate and DOR were very impressive, so the FDA approved the drug, as they did with nivolumab the year before. KEYNOTE-240 was the confirmatory trial; it was a second-line study in which patients were randomized to receive either pembrolizumab or placebo. The coprimary end points of the trial were PFS at the first interim analysis and OS at the end of the study.
The P values were set so low. If I remember correctly, the P value for PFS had to be less than .0020 and the P value for OS had to be less than .0174. If there are coprimary end points, the significance has to be higher. The data show a 3-month improvement in OS with pembrolizumab compared with sorafenib. However, that missed the prespecified P value by approximately 0.2 percentage points. [At the interim analysis], no difference in PFS was observed between the treatment arms. At the final analysis, the P value was .0022, not .0020.
What we [saw] from that trial [drives home] what we have learned from many previous trials: not everyone will respond to checkpoint inhibitors; but those who do, experience very long responses. The median PFS in that trial was 2.8 months, but for those who responded, it was in excess of 13 months. Therefore, we still need to identify who these [responding] patients are. I really don't think the study was negative. I'm not a statistician, and I respect them; it was so complex for me to understand.
Pembrolizumab is a great drug, but what's more exciting than its single-agent use is the breakthrough therapy designation that has been given to [its use in] combination with lenvatinib. The designation is based on a response rate of approximately 50%. I don't think we’re going to use single-agent checkpoint inhibitors [in the future]; we’re going to use a combination of either a checkpoint inhibitor and a TKI, like pembrolizumab and lenvatinib, or a checkpoint inhibitor and an antiangiogenic agent, like atezolizumab and bevacizumab. These [combinations] are going to change the care of patients with HCC.
Where do you see regorafenib (Stivarga) and cabozantinib (Cabometyx) fitting into this expanding treatment paradigm?
These were great drugs when they were introduced. There was the SHARP trial with sorafenib, and then there was the REFLECT trial with lenvatinib. Lenvatinib is a more effective and potent TKI. The REFLECT trial was a noninferiority trial that compared lenvatinib with sorafenib. The median PFS, time to progression, and ORR were significantly better with lenvatinib; that's an important point. If I have a patient with HCC who has symptomatic lung and bone metastases, I prefer to use lenvatinib because it [can lead to] an ORR of 30% versus 5% with sorafenib.
Lenvatinib has a little more toxicity, especially with regard to hand-foot [syndrome] and hypertension. We had sorafenib and lenvatinib in the first-line setting, [and then we went] to second-line therapy with regorafenib. Regorafenib is fluorinated sorafenib. By adding a fluoride atom, the metabolites hang around longer, thus making [the agent] more effective. Regorafenib was shown to be superior to placebo in patients who received sorafenib first. However, patients had to have had sorafenib for a few months [prior to treatment with regorafenib]. The amazing thing is that 50% of patients were able to take the 160-mg dose, which is not the case in colorectal cancer. Ultimately, regorafenib was approved based on data from the phase III RESORCE trial.
Then, there was the phase III CELESTIAL trial with cabozantinib. In the trial, cabozantinib was shown to be superior to placebo in patients who received up to 2 prior therapies; it is the only trial that included patients in the third-line setting. [Based on these results], cabozantinib [was] approved as second-line therapy.
We also have data from the phase III REACH-2 trial. The REACH study didn’t reach its primary end point. In the trial, ramucirumab (Cyramza) did not improve OS versus placebo in sorafenib-intolerant or -refractory patients. However, a preplanned subgroup analysis of patients who had alpha-fetaprotein (AFP) serum concentration of more than 400 [ng/mL] and Child-Pugh [class A] disease experienced a significant improvement in OS with the agent versus placebo.
REACH-2 met its end point. Results showed that those patients with Child-Pugh [class A] disease, good performance status, and AFP more than 400 [ng/mL] had a significantly better OS with ramucirumab. It's another drug to add to our treatment armamentarium. If the checkpoint inhibitors move into the first-line setting, all these drugs may become irrelevant because they have not been studied [in patients who have already received checkpoint inhibitors]. Therefore, we'll probably have to do these studies again in combination.
You also gave a presentation on cholangiocarcinoma at the State of the Science Summit™. What recent advances have been reported in this space?
Cholangiocarcinoma is what HCC was a few years ago; it's a disease no one really wanted to treat. Patients with cholangiocarcinoma are very sick. Moreover, it’s more than 1 disease. When we talk about cholangiocarcinoma, is it intrahepatic or extrahepatic? Is the gallbladder [involved]? We’ve learned that cholangiocarcinoma has many mutations. In fact, of all cancers, cholangiocarcinoma has the most known mutations. The problem is that we have not been able to target those mutations.
In the ClarIDHy study, patients with unresectable metastatic disease who received 1 or 2 lines of treatment were tested for IDH1 mutations. One of those lines of therapy had to be 5-fluorouracil or gemcitabine containing. We know that IDH1 is an enzyme that transforms isocitrate to alpha-ketoglutarate and then it moves into other reactions. However, in patients who have IDH mutations, there is another step. The alpha-ketoglutarate becomes 2-hydroxyglutarate, and 2-hydroxyglutarate is an oncometabolite; it induces the cell to become carcinogenic and start proliferating. We have many drugs to target [IDH mutations], 2 of which are on the market. We have the IDH1 inhibitor ivosidenib and the IDH2 inhibitor enasidenib (Idhifa). Both agents are approved for use in refractory acute myeloid leukemia.
In [ClarIDHy], investigators screened around 800 patients; around 24% had an IDH mutation. These patients were randomized to receive either ivosidenib or placebo. A significant improvement in PFS was observed in patients who received ivosidenib versus placebo. PFS served as the primary end point of the trial and patients who progressed on placebo were allowed to crossover to ivosidenib. Around 60% of patients crossed over. Therefore, the OS couldn't really be [accurately] analyzed. If you look at the whole group, there was no difference in OS. However, the investigators did a statistical analysis that took into account those patients who crossed over. When they took that into account, the OS benefit with ivosidenib was found to be statistically significant. This is a very important step forward for these patients, as there [were no agents available] to help them.
In December 2019, the FDA granted a priority review to pemigatinib for patients with FGFR2 fusions or rearrangements. What are your thoughts on that agent?
FGFR inhibitors have been shown to be effective. Pemigatinib also received a breakthrough designation. We are going to hear more about that agent. At the 2019 ESMO Congress, the ClarIDHy study was presented at the same time that the data for pemigatinib were presented. ClarIDHy received so much publicity that it overshadowed pemigatinib, but pemigatinib is a winner; there is no question about it.