Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice

Pinato, David J.; Marron, Thomas U.; Mishra‐Kalyani, Pallavi S.; Gong, Yutao; Wei, Guo; Szafron, David; Sharon, Elad; Saeed, Anwaar; Jun, Tomi; Dharmapuri, Sirish; Naqash, Abdul Rafeh; Peeraphatdit, Thoetchai; Gampa, Anuhya; Wang, Yinghong; Khan, Uqba; Muzaffar, Mahvish; Navaid, Musharraf; Lee, Chieh J.; Lee, Pei Chang; Bulumulle, Anushi; Yu, Bo; Paul, Sonal; Nimkar, Neil; Bettinger, Dominik; Hildebrand, Hannah; Abugabal, Yehia I.; Pressiani, Tiziana; Personeni, Nicola; D’Alessio, Antonio; Kaseb, Ahmed O.; Huang, Yi Hsiang; Ang, Celina; Schneider, Julie A.; Pillai, Anjana; Rimassa, Lorenza; Goldberg, Kirsten B.; Pazdur, Richard; Theoret, Marc R.; Lemery, Steven J.; Fashoyin-Aje, Lola A.; Cortellini, Alessio; Pelosof, Lorraine

doi:10.1016/j.ejca.2021.08.020

Cited by 48 publications

(47 citation statements)

References 34 publications

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“…Similarly, no HBV viral reactivation or changes in HBV medications were observed in a previously published retrospective analysis including patients with HCC [ 32 ]. In line with earlier findings [ 27 ], we observed a higher rate of grade ≥ 3 hepatitis in patients with chronic viral infectious etiology as compared to non-infectious etiologies.…”

Section: Discussionsupporting

confidence: 93%

“…Of note, we observed no episodes of liver decompensation during hepatic flares and we did not detect any impact of high-grade hepatitis on subsequent TTF. Additionally, it has been recently suggested that clinically significant adverse events, including hepatitis, might even correlate with improved outcomes during treatment with ICIs [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, patients who permanently discontinue treatment because of a treatment-related adverse event (including irAEs other than hepatitis) have a significantly shorter TTF than patients who experience liver failure or progressive disease. This is due to the timing of some treatment-related adverse events that may determine an earlier treatment discontinuation, while the oncologic outcomes measured by progression-free survival and OS do not appear to be detrimentally affected, as indicated by recent investigations [ 27 ]. In the event of high-grade hepatotoxicity, patients could be reassured that further doses of immunotherapy might be deferred without reducing the possibilities of treatment benefit.…”

Section: Discussionmentioning

confidence: 99%

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Hepatotoxicity in Patients with Hepatocellular Carcinoma on Treatment with Immune Checkpoint Inhibitors

Personeni

Pressiani

D’Alessio

et al. 2021

Cancers

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Risk factors for hepatic immune-related adverse events (HIRAEs) in patients with advanced/unresectable hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs) are unclear. We investigated: (i) clinical and morpho-pathological predictors of HIRAEs in 27 pretreatment tumor specimens, including surrogate biomarkers of the HCC immune class (based on intratumoral tertiary lymphoid structures, and glutamine synthase, CD3, and CD79 expression); and (ii) the relationship between HIRAE onset and subsequent treatment outcomes. Fifty-eight patients were included—20 (34%) received ICIs alone, and 38 (66%) received ICIs plus targeted agents as first- or further-line treatment. After a median time of 0.9 months (range, 0.4–2.7), nine patients (15.5%) developed grade ≥ 3 hepatitis, which was significantly associated with higher baseline ALT levels (p = 0.037), and an infectious HCC etiology (p = 0.023). ICIs were safely resumed in six out of nine patients. Time to treatment failure (TTF) was not significantly different in patients developing grade ≥ 3 hepatitis vs. lower grades (3.25 vs. 3.91 months, respectively; p = 0.81). Biomarker surrogates for the HCC immune class were not detected in patients developing grade ≥ 3 hepatitis. Grade ≥ 3 hepatitis has a benign course that does not preclude safe ICI reintroduction, without any detrimental effect on TTF.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hepatotoxicity in Patients with Hepatocellular Carcinoma on Treatment with Immune Checkpoint Inhibitors

Personeni

Pressiani

D’Alessio

et al. 2021

Cancers

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“…Moreover, compared with oral administration, it alleviated the side effects of sorafenib, avoiding damage to the capillary network of the fundus of the eye. Furthermore, a recent multi-center study showed a correlation between treatmentrelated adverse events and improved outcomes in patients with HCC receiving immune checkpoint inhibitors in clinical trials and in routine practice [125]. These findings could be useful to identify predictive biomarkers of toxicity and response.…”

Section: Current Gaps and Promising Approachesmentioning

confidence: 94%

HCC and Molecular Targeting Therapies: Back to the Future

et al. 2021

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Hepatocellular carcinoma (HCC) is one of the leading causes of death from cancer in the world. Recently, the effectiveness of new antiviral therapies and the HBV vaccine have reduced HCC’s incidence, while non-alcoholic steato-hepatitis is an emerging risk factor. This review focuses on antiangiogenic molecules and immune checkpoint inhibitors approved for HCC treatment and possible future approaches. Sorafenib was the first drug approved for the treatment of advanced HCC (aHCC) and it has been shown to increase survival by a few months. Lenvatinib, a multikinase inhibitor, has shown non-inferiority in survival compared with sorafenib and an improvement in progression-free survival (PFS). The combination of atezolizumab (an anti-PDL1 antibody) and bevacizumab (an anti-VEGF antibody) was the first drug combination approved for HCC, demonstrating improved survival compared with sorafenib (19.2 vs. 13.4 months). As a second line of therapy, three regimens (regorafenib, cabozantinib, and ramucirumab) have been approved for the treatment of aHCC after progression on sorafenib according to guidelines. Furthermore, nivolumab, pembrolizumab, and nivolumab plus ipilimumab have been approved by the FDA (2017, 2018, and 2020, respectively). Finally, immune target therapy, cancer vaccines, and epigenetic drugs represent three new possible weapons for the treatment of HCC.

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“…Recent studies have shown combination of PD-1 or PD-L1 inhibitors with anti-CTLa-4 drugs holds great effect, different immune checkpoints inhibitors (ICIs) elicit synergistic anti-tumor immune responses ( 12 , 13 ). Pinato and Marron illustrate for first time the positive relationship between trAEs and outcome from treatment with ICI in HCC ( 14 ). However, therapeutic effect of PD-1 blockade among different individuals is not yet clear.…”

Section: Introductionmentioning

confidence: 99%

A Patient With Failed Liver Transplantation After the Use of PD-1 Blockade Combined With Lenvaxen

et al. 2022

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Hepatocellular carcinoma (HCC) is a common malignant tumor with high extent of invasiveness. Its invasion process is closely related to complex tumor microenvironment and microvascular characteristics. Recently, immune combined targeted therapy has been applied to patients, combination therapy program with better effect needs to be explored. Atezolizumab combined Bevacizumab regimen in phase III clinical trial IMbrave150 was approved by U.S. Federal Drug Administration (FDA) for HCC treatment. This program is mostly used for liver malignant tumors have failed other treatments. Patients in terminal stage, overall curative has an unsatisfactory effect, survival time of patients is limited. Therefore, seeking best plan for combined treatment to improve patient's life quality and survival rate are still one of the most important clinical difficulties. This report describes a 37-year-old male who suffered from HCC repeatedly relapsed after hepatectomy. The patient received transcatheter arterial chemoembolization (TACE), microwave ablation (MWA), targeted therapy, and other combined treatments, all showed poor treatment effects. He received liver transplantation (LT) after receiving PD-1 blockade combined targeted therapy, eventually died due to severe immune rejection. It's first case of an allogeneic liver transplantation patient who received PD-1 blockade and Lenvaxen combined therapy. PD-1 blockade treatment and clinical observations of this case were summarized.

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Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice

Cited by 48 publications

References 34 publications

Hepatotoxicity in Patients with Hepatocellular Carcinoma on Treatment with Immune Checkpoint Inhibitors

Hepatotoxicity in Patients with Hepatocellular Carcinoma on Treatment with Immune Checkpoint Inhibitors

HCC and Molecular Targeting Therapies: Back to the Future

A Patient With Failed Liver Transplantation After the Use of PD-1 Blockade Combined With Lenvaxen

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