Immunotherapy combinations show promise for advanced liver cancer

Three checkpoint inhibitor immunotherapy regimens show promise for people with hepatocellular carcinoma (HCC), the most common type of liver cancer, according to a set of late-breaking presentations last week at the 2020 Digital International Liver Congress (ILC).

Chronic hepatitis B or C, heavy alcohol use, fatty liver disease and other causes of liver injury can lead to the development of cirrhosis and HCC. Liver cancer is often diagnosed late and is difficult to treat. It responds poorly to traditional chemotherapy, but several immunotherapy and targeted therapy drugs are being studied for this indication.

Checkpoint inhibitors are monoclonal antibodies that help the immune system fight cancer. Atezolizumab (Tecentriq), nivolumab (Opdivo) and pembrolizumab (Keytruda) interfere with PD-1, an immune checkpoint on T-cells that regulates immune function, thereby restoring T-cell activity against tumours. Ipilimumab (Yervoy) targets CTLA-4, a different immune checkpoint that suppresses T-cell multiplication.

Prof. Michel Ducreux of Gustave Roussy Cancer Center near Paris presented the latest findings from the phase III IMbrave150 trial (NCT03434379), which is evaluating atezolizumab plus bevacizumab (Avastin), a VEGF inhibitor that targets a protein that promotes the development of blood vessels that supply tumours.

The study included 336 people with unresectable (not removable by surgery) HCC who had not previously received systemic treatment. Just under half had hepatitis B and about one in five had hepatitis C. Three-quarters had cancer that had invaded the portal vein in the liver or had spread elsewhere in the body (metastasis).

Participants were randomly assigned to receive either intravenous infusions of atezolizumab plus bevacizumab every three weeks or twice-daily oral sorafenib (Nexavar), a targeted therapy that has been considered the standard of care.

Primary results recently published in the New England Journal of Medicine showed that atezolizumab plus bevacizumab reduced the risk of death by 42% compared with sorafenib. After a year on treatment, overall survival rates were 67% and 55%, respectively, and the median progression-free survival time was 6.8 versus 4.3 months, respectively. 

At ILC, Ducreux presented detailed safety results from the study, showing that although adverse event rates were roughly similar in the two arms – almost everyone experienced some side effects – the types of events differed.

Grade 3 or higher treatment-related adverse events occurred in 36% of patients assigned to atezolizumab plus bevacizumab versus 46% of those who received sorafenib. While 16% and 10%, respectively, discontinued treatment due to adverse events, temporary treatment interruption or dose reduction to manage side effects occurred more often.

The most common treatment-related events in the atezolizumab plus bevacizumab group were hypertension, protein in the urine, fatigue and AST liver enzyme elevation. The leading events in the sorafenib group were hand and foot syndrome (redness, swelling and pain on the palms and soles of the feet), diarrhoea, decreased appetite and hypertension.

Treatment that restores immune responses against cancer can also activate the immune system more broadly, leading to excessive inflammation that can harm organs throughout the body. Immune-mediated adverse events were more common in the atezolizumab plus bevacizumab arm, and more people in that group required management with corticosteroids.

Based on the strong efficacy results and patient-reported outcomes, as well as the in-depth safety evaluation presented here, the researchers concluded that atezolizumab plus bevacizumab "should be considered a new standard of care" for people with advanced liver cancer.

Prof. Bruno Sangro of Clinica Universidad de Navarra in Spain presented recent findings from the phase I/II CheckMate 040 trial (NCT01658878), which is evaluating nivolumab in different regimens, including in combination with ipilimumab.

The nivolumab plus ipilimumab analysis included 148 people with advanced HCC who had previously taken or could not tolerate sorafenib; most had metastatic cancer. Again, about half had hepatitis B and about 20% had hepatitis C.

The participants were randomised to receive one of three different regimens of nivolumab and ipilimumab. The most effective was 1 mg/kg nivolumab plus 3 mg/kg ipilimumab given by intravenous infusion every three week for four cycles, followed by nivolumab alone every two weeks until patients experienced disease progression or unacceptable side effects.

As reported last year in the Journal of Clinical Oncology, people assigned to this regimen had an overall response rate of 32%, including 8% with complete remission and 24% with partial responses. Another 18% had stable disease without further progression, yielding a disease control rate (response plus non-progression) of 54%. Overall survival rates were 61% after one year and 48% after two years, with a median overall survival time of 23 months.

Sangro presented longer follow-up data after a median of 30.8 months. Out of the initial group of 49 patients who started this regimen, eight (16%) were still on treatment, 25 (51%) stopped due to disease progression, 11 (22%) did so due to drug toxicities and five (10%) did so for other reasons. At 30 months, the overall survival rate was 37%.

He also presented a subgroup analysis based on prior treatment history, showing that longer prior treatment with sorafenib was associated with better outcomes. However, he noted that those previously treated for six months or less had less favourable characteristics at baseline.

The overall response rate was 29% among those who had taken sorafenib for six months or less, compared with 36% among those who had used it longer; there were two complete responses in each subgroup. The disease control rates were 46% and 64%, respectively. The respective median overall survival times were 19.2 and 25.5 months.

Treatment was described as well tolerated but adverse events were common: 38% had grade 3 or higher treatment-related adverse events and 5% stopped treatment for this reason. The most common side effects overall were skin rash and itching, while the most common severe effects were elevated AST and lipase (an enzyme that can indicate pancreas inflammation).

The researchers concluded that this nivolumab plus ipilimumab regimen "is a promising new treatment option for advanced HCC, independent of the duration of prior sorafenib administration."

Finally, Prof. Richard Finn of the University of California at Los Angeles reported results from a phase Ib trial of Keytruda plus lenvatinib (Lenvima), a targeted therapy that blocks VEGF receptors and enzymes which play a role in cancer growth.

The study (NCT03006926) included 100 people with unresectable HCC, most of whom had portal vein invasion or metastasis. They had not yet received systemic therapy for advanced liver cancer.

The overall response rate was 46% according to criteria commonly used to evaluate immunotherapy (modified RECIST). This included 11% with complete remission and 35% with partial responses. The median response duration was 8.6 months. Another 42% had stable disease, leading to a disease control rate of 88%.

The estimated median progression-free survival time, meaning time to either disease progression or death, was 9.3 months. Although overall survival data are not yet mature, the estimated median overall survival time for the group as a whole was 22.0 months, with a mortality rate of 34%. Among responders and people with stable disease, however, the median overall survival time could not yet be determined because a majority were still doing well.

Treatment was generally safe, but again side effects were common. About two-thirds had grade 3 or higher treatment-related adverse events. The most common side effects overall were hypertension, diarrhoea, fatigue, decreased appetite, hypothyroidism and hand and foot syndrome. The most common severe side effects were hypertension and AST elevation. About 20% stopped treatment due to adverse events.

The researchers concluded that pembrolizumab plus lenvatinib demonstrated promising anti-tumour activity, and that no new or unexpected toxicities occurred when combining the two drugs. Finn noted that the phase III LEAP-002 trial (NCT03713593), comparing this regimen against lenvatinib alone, has completed enrolment and is awaiting results.