A Phase I/II Study to Assess the Safety and Efficacy of Pazopanib and Pembrolizumab Combination Therapy in Patients with Advanced Renal Cell Carcinoma

Infante, J.; Hawkins, Robert E.; Voss, Martin H.; Perini, Rodolfo F.; Arkenau, Tobias; Voskoboynik, Mark; Aimone, Paola; Isabelle, Naëije; Reising, Albert; McDermott, David F.

doi:10.1016/j.clgc.2021.04.007

Cited by 20 publications

(9 citation statements)

References 46 publications

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“…Therefore, it is possible that the marked efficacy of the combination regimen was almost directly additive from that of the individual agents, or that the synergistic effect of anti-angiogenic agents on the anti-PD-1/PD-L1 antibodies in this combination regimen was limited. Furthermore, the combination regimens were often associated with severe toxicities, especially in the first three trials of pazopanil or sunitinib plus anti-PD-1 therapy ( 14 , 15 ) ( Table 1 ) . With the severe toxicities, further phase III trials have been prohibited.…”

Section: Discussionmentioning

confidence: 99%

Axitinib Reverses Resistance to Anti-Programmed Cell Death-1 Therapy in a Patient With Renal Cell Carcinoma

Yang

Huang

et al. 2021

Front. Immunol.

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Owing to broad and notable clinical anti-tumor activity, anti-programmed cell death-1 (PD-1)/anti-programmed cell death-ligand 1 (PD-L1) antibodies have been indicated for almost all types of cancer, and form a part of the current standard of care. However, a large proportion of patients do not respond to anti-PD-1/PD-L1 therapy (primary resistance), and responders often develop progressive disease (acquired resistance). The mechanisms of resistance are complex and largely unknown; therefore, overcoming resistance remains clinically challenging, and data on reversing anti-PD-1 resistance are scarce. Herein, we report the case of a 58-year-old woman with renal cell carcinoma associated with Xp11.2 translocation/transcription factor E3 gene fusion, who had already showed resistance to both anti-PD-1 monotherapy and standard-dose axitinib. However, she finally achieved a partial response with a continuous combination therapy comprising low-dose axitinib and anti-PD-1. We speculate that axitinib played a key role in reversing the primary resistance to anti-PD-1 therapy. Interestingly, we observed that the number of peripheral regulatory T cells increased after the standard-dose axitinib therapy, with accompanied tumor enlargement; however, after the dose was reduced, the number of regulatory T cells decreased gradually, and the tumor regressed. We also reviewed relevant literature, which supported the fact that low-dose axitinib might be more beneficial than standard-dose axitinib in assisting immunotherapy. Given that this is a single-case report, the immunomodulatory effect of axitinib requires further investigation.

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Section: Discussionmentioning

confidence: 99%

Axitinib Reverses Resistance to Anti-Programmed Cell Death-1 Therapy in a Patient With Renal Cell Carcinoma

Yang

Huang

et al. 2021

Front. Immunol.

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“…The incidence of drug-related grade 3 liver enzymes elevation was 33% for alanine aminotransferase and 25% for aspartate aminotransferase in our study. Other combinations of anti PD-1 monoclonal antibody and antiangiogenic TKI reported variable liver toxicity: nivolumab/sunitinib, nivolumab/pazopanib, pembrolizumab/pazopanib and pembrolizumab/axitinib reported 18, 20%, 60–70 and 8% of grade 3–4 elevated alanine aminotransferase, respectively [ 17 , 25 , 26 ]. In the dose escalation trial of nintedanib monotherapy, the DLTs were grade 3 or 4 liver enzyme elevations (2–5%), all reversible upon drug interruption [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Safety, recommended dose, efficacy and immune correlates for nintedanib in combination with pembrolizumab in patients with advanced cancers

Baldini¹,

Danlos

Varga³

et al. 2022

J Exp Clin Cancer Res

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Background We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425). Methods In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy. Results A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1–2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55–40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4+ PD1+ OX40+ T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP+ dendritic cells, CD3+ T cells and FOXP3+ Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4+ CXCR3+ CXCR5− memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels. Conclusion Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy. Trial registration ClinicalTrials.gov, NCT02856425. Registered August 4, 2016 — Prospectively registered.

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“…Given the relatively small numbers, the competitive role of concurrent targeted therapies cannot be completely discerned, as certain combinations of ICIs concurrent with tyrosine kinase inhibitors can synergize to develop high-grade hepatitis, as reported earlier in other disease settings [ 34 , 35 ]. Importantly, the incidence of high-grade hepatitis in this cohort was similar among patients receiving ICIs alone or ICIs plus targeted agents.…”

Section: Discussionmentioning

confidence: 99%

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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A Phase I/II Study to Assess the Safety and Efficacy of Pazopanib and Pembrolizumab Combination Therapy in Patients with Advanced Renal Cell Carcinoma

Cited by 20 publications

References 46 publications

Axitinib Reverses Resistance to Anti-Programmed Cell Death-1 Therapy in a Patient With Renal Cell Carcinoma

Axitinib Reverses Resistance to Anti-Programmed Cell Death-1 Therapy in a Patient With Renal Cell Carcinoma

Safety, recommended dose, efficacy and immune correlates for nintedanib in combination with pembrolizumab in patients with advanced cancers

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

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