CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: October 04, 2022
Expiration: October 03, 2023
Rachna T. Shroff, MD, MS:
Patients with BTCs tend to present with advanced disease and the prognosis is poor. 14 Regimens with fluoropyrimidines or gemcitabine with cisplatin have been used in advanced disease. Early-phase trials with CT and immunotherapy have been promising.
I was delighted to see updates from TOPAZ‑1 presented this year. TOPAZ‑1 was a double‑blind, randomized phase III trial investigating the role of durvalumab in addition to gemcitabine and cisplatin in patients with newly diagnosed advanced BTC.
The primary endpoint of this study was OS, which was significantly improved with durvalumab and CT vs placebo and CT (HR: 0.80; 95% CI: 0.66-0.97).15 Durvalumab is now approved in combination with gemcitabine and cisplatin for the treatment of adults with locally advanced or metastatic biliary tract cancer based on the TOPAZ-1 trial data. 16 A remaining question was whether individuals with intrahepatic cholangiocarcinomas (ICCs), extrahepatic cholangiocarcinomas (ECCs), and gallbladder cancers (GBCs) all derive benefit from the addition of immunotherapy with durvalumab. This TOPAZ-1 study update evaluated efficacy and safety outcomes by primary tumor location.17
Rachna T. Shroff, MD, MS:
Patients were a median of 62-65 years of age, with a majority having metastatic disease across the different tumor locations. Tumor PD-L1 expression was ≥1% in more than one half of patients across the different tumor locations. Most patients (56%) had ICC. A caveat is the limitations of small group sizes.
Rachna T. Shroff, MD, MS:
The addition of durvalumab to gemcitabine and cisplatin trended toward improving the median OS across each subgroup. The benefit in the overall patient population appeared to be driven by the improvement in ICC because the median OS was 13.5 months vs 11.5 months (HR: 0.76; 95% CI: 0.58-0.98).
With the ECC and GBC subgroups, the HRs for OS were not statistically significant. The median PFS was numerically improved across the subgroups, and response rates were also all in the 25% to 30% range with the addition of durvalumab (regardless of biliary tract malignancy). The OS benefit was consistent across different regions including Asia, Europe, and North America.
Rachna T. Shroff, MD, MS:
The adverse events were similar across primary tumor location arms, and there were no concerning new safety signals based on different tumor locations. There appeared to be numerically slightly more immune‑mediated adverse events in the ECC and GBC patient populations with durvalumab compared with placebo, but the population numbers were very small.
Rachna T. Shroff, MD, MS:
The investigators concluded from this subset analysis that the addition of durvalumab to gemcitabine and cisplatin was associated with an OS benefit across primary tumor location and geographic region, although the trial was not formally powered to draw these conclusions. The numbers of the ICC population really helped skew the median OS benefit in favor of a positive study. I still question the immunotherapy benefit in the ECC and GBC populations. The PFS and ORR outcomes trended toward improvement with the addition of durvalumab. There appeared to be a similar incidence of grade 3/4 TEAEs across the different tumor location groups.
I believe we have a new standard of care with the addition of durvalumab to gemcitabine and cisplatin for newly diagnosed advanced BTC. We need to better determine who is really deriving the benefit. I hope more thorough research with molecular analyses and immune profiling will help us discern the individual patient benefit as we move forward.
Joleen Hubbard, MD:
This updated analysis continues to support the use of durvalumab in combination with gemcitabine and cisplatin in the first‑line setting for advanced BTC, regardless of tumor location and geographic region. It is reassuring that no new safety signals were observed in this study.
Rachna T. Shroff, MD, MS:
The next study that we had the pleasure of seeing an update on was FIGHT‑202, which included the final phase II trial results. Pemigatinib is an oral FGFR inhibitor. After 17.8 months, pemigatinib had a 35.5% ORR in patients with previously treated cholangiocarcinoma with FGFR2 fusions or other rearrangements.18 Pemigatinib is approved by the FDA for adults with previously treated locally advanced or metastatic FGFR fusion‑positive cholangiocarcinoma.19 The findings from this update can help us to better understand the longer-term outcomes of treatment with pemigatinib.
This study was an open‑label, multicohort, single‑arm, phase II trial with the primary endpoint of ORR (N = 147). Cohort A included patients with FGFR2 fusions, which is what led to the accelerated approval in the United States. All participants had locally advanced or metastatic cholangiocarcinoma and had received a previous systemic therapy.20
Rachna T. Shroff, MD, MS:
More than one third of patients had ≥2 previous systemic therapies The majority had metastatic disease and an ECOG performance status of 0 or 1.
Rachna T. Shroff, MD, MS:
In cohort A, which had 108 patients with an FGFR2 fusion–positive tumor, the ORR was 37% after 42.9 months of follow‑up, which confirms that FGFR2 is a targetable alteration. Of importance, the disease control rate in this cohort was 82%, so even for those who did not respond, the majority had stabilization of disease. The median DoR was 9.1 months, so this was not a short‑lived response, with a median PFS of 7 months. The median OS was 17.5 months in the patients who had FGFR2 fusions and received pemigatinib. Cohort B and cohort C had very minimal activity, so it is important to recognize that the tumors with FGFR2 fusions are where the benefit is observed in cholangiocarcinoma.
Rachna T. Shroff, MD, MS:
Updated safety results did not reveal new safety signals. Most patients experienced grade 1/2 TEAEs such as hyperphosphatemia, alopecia, and diarrhea. These are class effects of FGFR inhibition.21
Rachna T. Shroff, MD, MS:
Pemigatinib continued to provide durable responses with an ORR of 37% and an extended OS in patients who had previously treated advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements. The ORR of 37% is consistent with the efficacy of other FGFR inhibitors evaluated in FGFR2 fusion–positive cholangiocarcinoma.21 The median OS of longer than 17 months is good to see in a patient population that, historically, even with gemcitabine‑based CT, demonstrates a median OS of approximately 11 months. The efficacy is well balanced by the fact that pemigatinib continues to have a manageable safety profile. The most frequent TEAEs were class effects like hyperphosphatemia, alopecia, and diarrhea.
This study highlights the need for molecular testing in all patients with cholangiocarcinoma; these patients need broad‑based biomarker testing at the time of diagnosis.
Joleen Hubbard, MD:
For the second‑line setting of cholangiocarcinoma, these results appear very meaningful. I agree that we really need to test all cholangiocarcinoma patients with NGS to identify fusions and translocations because those patients may benefit from these medications in terms of OS. This agent and similar agents have revolutionized the treatment of this disease.
Rachna T. Shroff, MD, MS:
HCC is the fastest-rising cause of cancer-related mortality in the United States.22 It typically occurs in the setting of cirrhosis. Some underlying associated conditions include hepatitis B virus and nonalcoholic fatty liver disease (NAFLD). OS rates are poor, particularly in unresectable HCC.22 In recent years, systemic approaches with tyrosine kinase inhibitors (eg, sorafenib, lenvatinib, regorafenib) or immunotherapies (eg, atezolizumab, durvalumab, nivolumab, pembrolizumab) have been studied. A phase I/II study evaluated tremelimumab (a CTLA4 antibody) and durvalumab (a PD-L1 antibody) as combination therapy or monotherapy in patients who had progressed on, were intolerant to, or refused sorafenib.23
The investigators concluded that the combination regimen with tremelimumab as a single 300-mg dose with durvalumab 1500 mg every 4 weeks (the single tremelimumab regular interval durvalumab, or STRIDE regimen) demonstrated activity and manageable safety warranting a follow-up trial.23,24
The HIMALAYA phase III, multicenter, open-label study was designed to compare the STRIDE regimen vs durvalumab monotherapy vs sorafenib in patients with systemic treatment-naive unresectable HCC. 24 The primary outcome was OS with STRIDE vs sorafenib.24
Rachna T. Shroff, MD, MS:
This specific HIMALAYA trial exploratory analysis evaluated efficacy outcomes, like OS and ORR, and safety outcomes in the context of baseline albumin-bilirubin (ALBI) score.25
An ALBI score is calculated for an individual patient using bilirubin and albumin. It is described as an emerging alternative objective measure of liver impairment.26 Patients (N = 1171) with Child-Pugh class A, unresectable HCC, and who had received no previous systemic therapy were randomized in a 1:1:1 into the 3 arms of the STRIDE regimen vs durvalumab monotherapy vs sorafenib. Treatment was continued until disease progression.
Rachna T. Shroff, MD, MS:
Lower ALBI grades indicate lower risk of death or adverse liver-related outcomes. It is important to point out that most HIMALAYA study patients had an ALBI grade 1 score, with more than 50% of patients in each arm having a grade 1 score and fewer than one half with ALBI grade 2. Very few patients (≤0.5%) had an ALBI grade 3 score.
Rachna T. Shroff, MD, MS:
Patients were primarily male (80%-91%) with a mean age of 61-65 years. In total, 37% to 45% of patients had unresectable HCC of nonviral etiology. Most patients (54%-70%) were fully active with an ECOG performance status 0.
Rachna T. Shroff, MD, MS:
When we look at STRIDE vs sorafenib in terms of OS by ALBI grade, we see that median OS of the STRIDE regimen in ALBI grade 1 patients was longer than 23 months compared with 19 months in the sorafenib arm (HR: 0.79; 95% CI: 0.62-1.01). Here, the HR just barely crossed 1, but the curves are separating and staying separated. Similarly, in the ALBI grade 2 and 3 patients there was a numerical improvement from 9.7 months to 11.3 months (HR: 0.83; 95% CI: 0.65-1.05). ALBI grade 1 patients, because of the underlying improved liver function, had a better OS than in the sorafenib arm, which is important to point out.
Rachna T. Shroff, MD, MS:
In the ALBI grade 1 patients, there was an ORR in the STRIDE arm of 21.7% vs a slightly lower response of 18.3% in the STRIDE arm for ALBI grade 2/3 scores. It is important to recognize that the ORR in the STRIDE arm was consistent with the ORR in the full analysis set, in that ORR is approximately 20%, even when broken down by ALBI grade. Similarly, the median DoR with STRIDE appeared consistent between the ALBI grades and the full analysis set (22-27 months.)
Rachna T. Shroff, MD, MS:
Safety is an issue, especially when considering worsening liver function based on ALBI grade. Any immune‑mediated TEAE occurred in 43.5% in the STRIDE regimen of ALBI grade 1 patients, which was slightly higher than the full analysis set where the rate was 35.8%. It will be important to understand who these patients are that are having immune‑mediated TEAEs and learn more about the nature of the adverse events. Following this out more longitudinally will be key.
Rachna T. Shroff, MD, MS:
The investigators also evaluated whether there were changes in liver function over time. In general, patients were able to preserve liver function when they were on the STRIDE regimen and/or durvalumab regimens.
Rachna T. Shroff, MD, MS:
The efficacy benefit observed with the STRIDE regimen vs sorafenib appeared to be consistent regardless of baseline ALBI grade. The safety profiles were very similar across the subgroups as well, especially when compared with the full analysis set. An important point to highlight is that liver function appeared to be stable over time in the STRIDE and durvalumab arms. This shows that these regimens were not having a negative impact on liver function. Of more importance, perhaps by treating the disease, we can preserve liver function in patients with underlying cirrhosis.
The findings from this analysis continue to support the use of the STRIDE regimen as a new option for patients with unresectable HCC. We need to better understand the role ALBI scoring can play in stratifying patients, but it should not necessarily play a part in the decision making of whether to use STRIDE.
Joleen Hubbard, MD:
For many years, trials only enrolled participants with Child‑Pugh class A, but this analysis specifically looked at classes A5, A6, and B7 and characterized participants by ALBI grade. ALBI grading is similar to the Child‑Pugh classes in terms of trying to categorize the liver function and the risk of adverse events and poor survival. In this trial, the survival benefit was maintained regardless of the ALBI grade. There were similar results in safety and the maintenance of liver function over time, which is very important for this patient population.
The ORRs and OS rates looked slightly better for the lower-grade or lower‑risk patient population, but still had a meaningful benefit compared with sorafenib. These findings support the use of tremelimumab and durvalumab in this patient population in the first‑line setting and its potential advantage over sorafenib, regardless of baseline liver function. The question remains about how this combination immunotherapy compares with atezolizumab/bevacizumab, which has become the standard of care in the first‑line setting. I believe this regimen will be reserved for patients who are not candidates for the bevacizumab/atezolizumab regimen, such as someone with esophageal varices. This may be a more appropriate regimen for that patient population.
Rachna T. Shroff, MD, MS:
CheckMate040 was an open-label, multicohort, phase I/II trial evaluating nivolumab and ipilimumab in patients with advanced HCC with intolerance to or progression on sorafenib. This study randomized 148 patients into 3 arms with different weight-based dosing schedules: nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (Arm A) or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (Arm B) every 3 weeks for 4 doses followed by 240 mg every 2 weeks; or nivolumab 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks (Arm C). The primary endpoints were safety and tolerability, and ORR. The Arm A dosing regimen was approved by the FDA for patients with HCC previously treated with sorafenib based on an ORR of 32% (95% CI: 20%-47%) at a median follow-up of 30.7 months.27 The currently presented results are the 5-year update.28
Rachna T. Shroff, MD, MS:
At 5 years, the ORR in Arm A was preserved at 34%, with a median DoR longer than 50 months and a median PFS of 6.8 months. Over 5 years, we see continued and consistent efficacy.
Rachna T. Shroff, MD, MS:
The median OS in Arm A was 22.8 months in the primary analysis and in the long‑term follow-up it was 22.2 months, with a 60‑month OS rate of 29%. To reiterate, 29% of patients were alive at 5 years, which is truly incredible when considering this disease. There was a question of whether CD8 positivity plays a role in median OS outcomes but there did not seem to be a difference when groups were stratified by CD8 positivity. The 3‑year OS rate in the best overall responders was 87% in Arm A. People who were responding had a very meaningful durable OS.
Rachna T. Shroff, MD, MS:
Of importance, in terms of TRAEs, there were no new safety signals that came out in the 5‑year update.
Rachna T. Shroff, MD, MS:
When looking at the endocrine immune‑mediated adverse events and anything requiring immune‑modulating medication, 35% of patients had any‑grade rash in Arm A; no new findings were identified in long‑term follow-up.
Rachna T. Shroff, MD, MS:
At the 5‑year follow-up, Arm A demonstrated durable responses and prolonged survival in patients with advanced HCC who have previously received sorafenib, including a 29% OS rate at 60 months. We have not observed similar findings in the past. There were no new or emerging safety signals. With this level of long‑term follow-up, these findings suggest that Arm A could be a useful regimen in the second‑line setting after patients receive sorafenib. That said, it is important to keep in mind that many patients no longer receive sorafenib in the frontline setting. Questions remain about how to integrate this regimen in a later-line setting if someone already received an immunotherapy-based regimen. We await the findings from the recently completed nivolumab/ipilimumab frontline trial.
Joleen Hubbard, MD:
I agree, that the pivotal question is how the nivolumab/ipilimumab regimen, in the second‑line setting, will fall in line with the available agents that we have. If patients are starting out with bevacizumab/atezolizumab or, potentially, durvalumab/tremelimumab in the first‑line setting, then where will nivolumab/ipilimumab be positioned? It is great that we have several options in the second-line setting after sorafenib. The challenge is going to be sequencing these treatment options. More research, including the next study, may help determine if there is an optimal sequence strategy in certain patient populations.
Rachna T. Shroff, MD, MS:
In addition to the previously discussed HIMALAYA trial,24,25 2 other recent trials in unresectable HCC compared immunotherapy in combination with or vs multikinase inhibitors.29,30 Subgroup analyses of these studies suggested potential differences in response based on HCC etiology.
Rimini and colleagues presented a retrospective analysis of prospectively collected data in patients with nonviral HCC who received atezolizumab and bevacizumab vs lenvatinib.31 It included a broad population of 759 patients from 36 centers in 4 countries. The primary objective was OS. The population was broken down into subsets focusing on patients who had NAFLD and nonalcoholic steatohepatitis (NASH) vs non‑NAFLD and non-NASH subsets. The investigators were evaluating for nonviral HCC and whether the NAFLD patient population has different outcomes with these regimens.
Rachna T. Shroff, MD, MS:
For the overall population (N = 759), the lenvatinib median OS was 17.8 months vs 12.1 months in the atezolizumab and bevacizumab arm (unadjusted HR: 0.71; 95% CI: 0.5-1.06). There was improvement in the median PFS with lenvatinib (unadjusted HR: 0.64; 95% CI: 0.49-0.84). When the analyses were adjusted for clinical covariates, the HRs were statistically significant in favor of lenvatinib.
Rachna T. Shroff, MD, MS:
For the NAFLD and NASH population (n = 336), the lenvatinib arm had a median OS of 21.2 months vs 12.2 months in the atezolizumab and bevacizumab arm (unadjusted HR: 0.46; 95% CI: 0.25-0.88).
Again, there was improvement in the median PFS.
A univariate analysis demonstrated that other factors were associated with longer OS, including age, Barcelona Clinic Liver Cancer class, ALBI grade, neutrophil to lymphocyte ratio, and previous transarterial chemoembolization. Of course, there are multiple factors to consider in what could be driving this benefit.
Rachna T. Shroff, MD, MS:
The difference between lenvatinib and atezolizumab plus bevacizumab is not as striking with the non‑NAFLD/NASH population, where the median OS was 14.9 months with lenvatinib vs 11.6 months with atezolizumab and bevacizumab (unadjusted HR: 0.96; 95% CI: 0.6-1.54). There were no differences in unadjusted PFS or adjusted OS and PFS. Perhaps the NAFLD/NASH population is driving the difference in the overall patient population.
Rachna T. Shroff, MD, MS:
This retrospective evaluation included a large subset of patients with nonviral HCC. It appeared lenvatinib was associated with improved outcomes compared with atezolizumab and bevacizumab, but that the benefit was most notable in patients with NAFLD and NASH‑related HCC. It is important to highlight that prospective trials are really needed to validate these findings. It is a hypothesis‑generating statement to say that in patients with nonviral HCC, perhaps a multitargeting tyrosine kinase inhibitor like lenvatinib would be more beneficial than a combination of an immunotherapy and VEGF inhibitor. As we start to ask these questions and better understand these subsets, we will, hopefully, be able to answer these in a prospective manner. If etiology is absolutely driving outcomes, it will be important, as we have more and more therapies available to us, to know what the ‘right’ first‑line therapy could be.
Joleen Hubbard, MD:
I agree that this retrospective study is very interesting and hypothesis generating. It needs to be validated in a prospective study in a randomized population, but it is exciting and may identify a patient population that could benefit from starting with lenvatinib or a multikinase inhibitor first. If these benefits are validated, it may help us narrow down how to strategically use the multitude of agents that we now have approved for HCC.
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