Additional Second- and Third-Line Treatment Options in HCC

Anthony El-Khoueiry, MD: Lastly, to consider second- and third-line options, we know that both nivolumab and pembrolizumab are anti–PD-1 antibodies and have accelerated approval as single agents in second-line post-sorafenib HCC [hepatocellular carcinoma]. Those accelerated approvals in the post-sorafenib era were based on single-agent activity with response rates in the 15%-to-20% range for both of these agents with durable responses. One of the challenges, though, is that the KEYNOTE-240 phase 3 study, which was the validation study for pembrolizumab post sorafenib and randomized patients to pembrolizumab versus placebo, was not statistically significant. It did not reach statistical significance as far as overall survival. The study had shared end points, coprimary end points of overall survival and PFS [progression-free survival] and had multiple interim looks.

A lot of the study was spent on that—to meet statistical significance, the P value had to be below .0174—and the P value was actually just above that at .02. Even though the curve separated, the median OS [overall survival] with pembrolizumab was 13 months, and with placebo it was 10 months, so we know there was clinical activity for pembrolizumab. It did not reach statistical positivity, statistical significance, and therefore is a negative trial by definition.

To complicate things further, it’s important to note that if a patient is treated with atezolizumab and bevacizumab, it would not make sense to go to nivolumab or pembrolizumab because the patient already progressed on anti–PD-L1 therapy, and we have no evidence that switching to anti–PD-1 therapy would actually have activity in that setting.

The last second-line option I would mention is the combination of nivolumab and ipilimumab. This has also received accelerated approval in 2020. This was a cohort of the CheckMate040 trial, in which 3 different dosing and schedule combinations of NIVO [nivolumab] and IPI [ipilimumab] were evaluated. The combination that received accelerated approval is with nivolumab 1 mg and ipilimumab 3 mg/kg every 3 weeks given together for 4 cycles, and the patients are maintained on nivolumab single agent.

The objective response rate based on RECIST [Response Evaluation Criteria in Solid Tumors] 1.1 was in the low-30% range for this combination, and the median overall survival post sorafenib was an impressive 22 months with this combination. All patients had Child-Pugh stage A and a good performance status. It’s also important to note that with this combination, there is a higher risk of toxicity and immune-mediated events. The grade 3 and 4 events occurred in 53% of patients, and roughly half the patients had to have a steroid for immune-mediated adverse events. Of course, the most common ones were dermatitis, but there was also some colitis, hepatitis, and pneumonitis. This is a combination that has to be given to the right patient, and the patients have to be managed carefully to ensure that they can tolerate it and are treated adequately.

In regard to alpha-fetoprotein [AFP], especially in the second-line setting, it is important to note that all the agents I covered analyzed their data or had an analysis of the studies that led to their approval based on AFP above and below 400 ng/mL. It’s important to note that all these agents were noted to have activity independent of AFP level, regorafenib, the anti–PD-1 antibody, as well as cabozantinib. For cabozantinib, there was an additional analysis that looked at AFP response and showed that the frequency of AFP response was significantly higher in the cabozantinib arm compared with the placebo naturally. But what was intriguing in that analysis is that for the AFP responders, the median overall survival with cabozantinib was 16 months compared with the nonresponders, where the median overall survival was 9 months. In understanding AFP response with these systemic agents and the dynamic changes of AFP, this is going to be an area of further investigation, and it’s important to keep in mind going forward.

Transcript edited for clarity.

Case: A 69-Year-Old Man with Stage 4 Hepatocellular Carcinoma

Initial presentation

• A 69-year-old man presented with vague right upper quadrant abdominal discomfort, decreased appetite and occasional nausea and vomiting
• PMH: diabetes, medially controlled; hepatitis B virus diagnosed and treated 8 years ago
• SH: moderate amount of alcohol use (2-3 drinks a day)
• PE: abdominal discomfort on palpation
  
  

Clinical workup

• Labs: AFP 425 ng/mL, bilirubin 1.2 mg/dL, AST 102 U/L, ALT 116 U/L, ALP 380 U/L, INR 1.6, albumin 3.6 g/dL, BUN 15 mg/dL, creatinine 1.5 mg/dL, plt 205,000
• HBV+, HCV-
• Abdominal ultrasound revealed 2 hepatic lesions
• Chest/abdominal/pelvic CT scan confirmed 2 lesions in the right hepatic lobe measuring 3.2 cm and 5.5 cm, a suspicious lesion in the left lung lobe, and wide-spread lymphadenopathy noted
• Biopsy findings showed grade 3 HCC with marked fibrosis
• Surgical consult: unresectable due to tumor size and location
• Child-Pugh A; BCLC stage C
• ECOG 1
  
  

Treatment and Follow-Up

• Treatment with atezolizumab + bevacizumab was initiated
  • First imaging shows stable disease at 2 months; imaging at 4-month follow-up showed 2 new lung lesions
  • Treatment was subsequently changed to cabozantinib 60 mg PO qDay