Lenalidomide for Second-line Treatment of Advanced Hepatocellular Cancer

Safran, Howard; Charpentier, Kevin P.; Kaubisch, Andreas; Mantripragada, Kalyan; Dubel, Gregory J.; Perez, Kimberly; Faricy-Anderson, Katherine E.; Miner, Thomas J.; Eng, Yoko; Victor, Joel; Plette, Angela; Espat, Joseph; Bakalarski, Pamela; Wingate, Patti; Berz, David; Luppe, Denise; Martel, Diane; Rosati, Kayla; Aparo, Santiago

doi:10.1097/coc.0b013e3182868c66

Cited by 22 publications

(12 citation statements)

References 23 publications

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“…Lenalidomide was well tolerated, with rare grade 3 toxicities. The PR rate was 15%, including 2 patients with a durable response of 32 and 36 months [16]. …”

Section: Assessment Analysis and Discussionmentioning

confidence: 99%

Phase I Study of Lenalidomide and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

et al. 2016

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Lessons Learned Combination therapies in patients with hepatocellular carcinoma can be associated with overlapping toxicity and are therefore poorly tolerated. Using sorafenib at the maximum tolerated dose can lead to a higher incidence of toxicities. Consequently, combination studies might evaluate sorafenib at alternative schedules or doses to improve tolerance, recognizing this could affect sorafenib efficacy. Although this combination was poorly tolerated, it does not exclude further evaluation of new-generation immunomodulator drugs or immune checkpoint inhibitors in the hope of optimizing tolerance and safety. Background. Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), and to date, no combination therapy has demonstrated superior survival compared with sorafenib alone. The immunosuppressive microenvironment in HCC is a negative predictor for survival. Lenalidomide is an immunomodulator and antiangiogenic agent, with limited single-agent efficacy in HCC. Based on these data, we designed a phase I study of sorafenib plus lenalidomide to determine the safety and preliminary antitumor activity of this combination. Methods. This was an open-label, phase I study with a 3+3 dose escalation/de-escalation design. The starting dose of sorafenib was 400 mg p.o. b.i.d. and of lenalidomide was 15 mg p.o. daily with a planned dose escalation by 5 mg per cohort up to 25 mg daily. Dose de-escalation was planned to a sorafenib dose of 400 mg p.o. daily combined with two doses of lenalidomide: 10 mg p.o. daily for a 28-day cycle (cohort 1) and 10 mg p.o. daily for a 21- or 28-day cycle (cohort 2). Patients with cirrhosis, a Child-Pugh score of A-B7, and no previous systemic therapy were eligible. Results. Five patients were enrolled. Their median age was 56 years (range 39–61), and the ECOG status was 0–2. Four patients were treated at dose level (DL) 1. Because of the poor tolerance to the combination associated with grade 2 toxicities, one more patient was treated at DL −1. No dose-limiting toxicity was observed as specified per protocol. The most common toxicities were nausea, anorexia, pruritus, elevated liver enzymes, and elevated bilirubin. Three patients experienced one or more of the following grade 3 toxicities: fatigue (DL 1), increased bilirubin (DL 1), skin desquamation (DL −1), and elevated transaminase levels (DL 1). The median duration of therapy was 1 cycle (range 1–3). All patients discontinued the study, 4 because of progressive disease and 1 by patient preference. The best confirmed response was progressive disease. The median progression-free survival was 1.0 month (95% confidence interval 0.9–2.8), and the median overall survival was 5.9 months (95% confidence interval 3.68–23.4). Conclusion. In our small study, the combination of lenalidomide and sorafenib was poorly tolerated and showed...

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“…Lenalidomide was well tolerated, with rare grade 3 toxicities. The PR rate was 15%, including 2 patients with a durable response of 32 and 36 months [16]. …”

Section: Assessment Analysis and Discussionmentioning

confidence: 99%

Phase I Study of Lenalidomide and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

et al. 2016

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“…Lenalidomide has been evaluated in a phase II study after sorafenib failure or intolerance, with PR of 15% and 7.6 months of mOS [82]. In an orthotopic HCC model, lenalidomide plus sorafenib showed an interesting tumor growth inhibition, with a significant increase of T cytotoxic IFN-γ infiltrating tumor cells [83].…”

Section: Indirect Immunological Strategiesmentioning

confidence: 99%

Immunotherapeutic approaches for hepatocellular carcinoma

Longo¹,

Gaspar²,

Casadei-Gardini

et al. 2017

Oncotarget

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Hepatocellular carcinoma (HCC) is a cancer with a high mortality rate due to the fact that the diagnosis usually occurs at anadvanced stage. Even in case of curative surgical treatment, recurrence is common. Sorafenib and regorafenib are the only therapeutic agents that have been demonstrated to be effective in advanced HCC, thus novel curative approaches are urgently needed. Recent studies focus on the role of immune system in HCC. In fact, the unique immune response in the liver favors tolerance, which can represent a real challenge for conventional immunotherapy in these patients. Spontaneous immune responses against tumor antigens have been detected, and new immune therapies are under investigation: dendritic cell vaccination, immune-modulator strategy, and immune checkpoint inhibition. In recent years different clinical trials examining the use of immunotherapy to treat HCC have been conducted with initial promising results. This review article will summarize the literature data concerning the potential immunotherapeutic approaches in HCC patients.

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“…In the present study, cisplatin significantly reduced MDA-MB-231 cell viability at an IC 50 value of 7.8 µM. On the other hand, it is controversy and debatable whether lenalidomide can be used to control solid tumors (14,16), although lenalidomide significantly inhibited growth of the chronic lymphocytic leukemia cells (19). In the present study, we further confirmed that lenalidomide alone had only a minimal effect on MDA-MB-231 cell viability, even at a very high dose of 320 µM, far beyond the clinically achievable concentration in humans (20).…”

Section: Discussionmentioning

confidence: 88%

“…In addition to the anti-angiogenic and immunomodulatory properties, lenalidomide has been shown to have cytotoxic effect in tumor cells (13). In clinical trials, lenalidomide was either used as a single agent or in combination with other chemotherapeutic drugs in many solid tumors; for example, Said et al showed that lenalidomide in combination with 5-fluorouracil, leucovorin, and oxaliplatin was able to control advanced colorectal cancer (13), while Safran et al assessed the activity and efficacy of lenalidomide on advanced hepatocellular cancer that was previously treated with sorafenib (14), where six out of 40 patients (15%) achieved a partial response, including two patients (5%) had stable disease for more than 32 months (14). These data indicate that lenalidomide could be more effective in combination with chemotherapeutic drugs, such as gemcitabine or docetaxel (12,15).…”

Section: Introductionmentioning

confidence: 99%

Lenalidomide improvement of cisplatin antitumor efficacy on triple-negative breast cancer cells inï¿½vitro

et al. 2018

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Abstract.Lenalidomide is an immunomodulatory drug and possesses anti-angiogenic and immunomodulatory activities against multiple myeloma. The present study assessed the in vitro effect of lenalidomide combined with cisplatin on MDA-MB-231, a triple-negative breast cancer (TNBC) cell line and explored the underlying molecular mechanism of this combination. Cell viability, apoptosis and the protein expression of phosphorylated (p) and total extracellular signal-regulated kinase (ERK), B-cell lymphoma-2 (Bcl-2), caspase-3, cleaved poly-adenosine diphosphate-ribose polymerase (cPARP), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were measured in MDA-MB-231 cells treated with different concentrations of lenalidomide, cisplatin and their combination using different biochemical assays. Lenalidomide demonstrated no significant effect on the cell viability of MDA-MB-231 cells, even at high concentrations, whereas lenalidomide in combination with cisplatin, significantly reduced cisplatin IC 50 from 7.8 to 3.0 µM in MDA-MB-231 cells. In addition, lenalidomide and cisplatin in combination significantly induced cell apoptosis by 1.6-and 1.38-fold, respectively compared with lenalidomide and cisplatin alone (P<0.05). The expression levels of VEGF, bFGF and Bcl-2 proteins were significantly reduced (P<0.01), whereas caspase-3 and cleaved PARP expression were significantly increased in MDA-MB-231 cells treated with the combination compared to those treated with single agents (P<0.01). Lenalidomide treatment alone significantly reduced the p-ERK level compared with the control (P<0.05) and cisplatin treatment alone significantly increased it (P<0.01), however treatment with them in combination significantly reduced the p-ERK level in MDA-MB-231 cells compared with cisplatin treatment alone (P<0.05). In conclusion, the present study provides the basis for using lenalidomide in combination with cisplatin in TNBC therapy.

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Lenalidomide for Second-line Treatment of Advanced Hepatocellular Cancer

Abstract: Lenalidomide can be administered to patients with advanced HCC and hepatic dysfunction. Promising, and in a small percentage of patients, durable activity has been demonstrated. Investigations are needed to explore the mechanism of action of lenalidomide in HCC.

Cited by 22 publications

References 23 publications

Phase I Study of Lenalidomide and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Phase I Study of Lenalidomide and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Immunotherapeutic approaches for hepatocellular carcinoma

Lenalidomide improvement of cisplatin antitumor efficacy on triple-negative breast cancer cells inï¿½vitro

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