Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial

Matasar, Matthew J.; Capra, Marcelo; Özcan, Muhıt; Lv, Fangfang; Li, Wei; Yáñez, Eduardo; Sapunarova, Katya; Lin, Tongyu; Jin, Jie; Jurczak, Wojciech; Hamed, Aryan; Wang, Ming-Chung; Baker, Ross; Bondarenko, Igor; Zhang, Qingyuan; Feng, Jifeng; Geißler, Klaus; Lazaroiu, Mihaela; Saydam, Güray; Szomor, Árpád; Bouabdallah, Krimo; Galiulin, Rinat; Uchida, Toshiki; Soler, Lidia Mongay; Cao, Anjun; Hiemeyer, Florian; Mehra, Aruna; Childs, Barrett H.; Shi, Yuankai; Zinzani, Pier Luigi

doi:10.1016/s1470-2045(21)00145-5

Cited by 99 publications

(94 citation statements)

References 26 publications

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“…Numerous PAM inhibitors have been investigated in over 1150 clinical trials as of April 2021. Of these, the following molecules have been approved by the Food and Drug Administration at this time: the mTOR inhibitors everolimus [ 33 ] and temsirolimus [ 34 ]; the pan-PI3K inhibitor copanlisib [ 35 ]; the PI3Kδ inhibitors idelalisib [ 36 ] and duvelisib [ 37 ]; and the PI3Kα inhibitor alpelisib for second-line treatment of HR + metastatic breast cancer combined with fulvestrant [ 38 , 39 ]. Two important characteristics may differentiate M2698 from other PAM inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer

et al. 2021

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Background The PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies. Methods M2698 was administered as monotherapy (escalation, 15–380 mg daily; food effect cohort, 240–320 mg daily) and combined with trastuzumab or tamoxifen. Results Overall, 101 patients were treated (M2698, n = 62; M2698/trastuzumab, n = 13; M2698/tamoxifen, n = 26). Patients were predominantly aged < 65 years, were female, had performance status 1 and were heavily pretreated. There was a dose- and concentration-dependent inhibition of pS6 levels in peripheral blood mononuclear cells and tumor tissue. M2698 was well tolerated; the most common treatment-emergent adverse events were gastrointestinal, abnormal dreams and fatigue (serious, attributed to M2698: monotherapy, 8.1%; M2698/trastuzumab, 7.7%; M2698/tamoxifen, 11.5% of patients). The recommended phase 2 doses of M2698 were 240 mg QD (monotherapy), 160 mg QD (M2698/trastuzumab) and 160 mg QD/240 mg intermittent regimen (M2698/tamoxifen). In the monotherapy cohort, 27.4% of patients had stable disease at 12 weeks; no objective response was noted. The median progression-free survival (PFS) durations in patients with PAM pathway alterations with and without confounding markers (KRAS, EGFR, AKT2) were 1.4 months and 2.8 months, respectively. Two patients with breast cancer (M2698/trastuzumab, n = 1; M2698/tamoxifen, n = 1) had partial response; their PFS durations were 31 months and 2.7 months, respectively. Conclusions M2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance. Trial registration ClinicalTrials.gov, NCT01971515. Registered October 23, 2013.

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Section: Discussionmentioning

confidence: 99%

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer

et al. 2021

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“…Most recently, copanlisib has been combined with rituximab in a phase-III trial in patients with R/R indolent lymphomas, including FL, demonstrating 81% ORR (34% CR) in all indolent histologies vs. 48% ORR (15% CR) in the rituximab monotherapy arm. In the 184 FL patients included in the copanlisib-rituximab arm, median PFS was 22 vs. 18.7 months for the 91 FL patients in the rituximab arm (Matasar et al, 2021). However, nearly half of all patients had severe adverse events, including hyperglycemia and hypertension, while less than 20% patients in the singleagent rituximab arm had serious adverse events.…”

Section: Agents Targeting Lymphoma Metabolismmentioning

confidence: 99%

Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies

Serganova

Chakraborty

Yamshon

et al. 2022

Front. Cell Dev. Biol.

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B-cell non-Hodgkin lymphomas (B-NHLs) are highly heterogenous by genetic, phenotypic, and clinical appearance. Next-generation sequencing technologies and multi-dimensional data analyses have further refined the way these diseases can be more precisely classified by specific genomic, epigenomic, and transcriptomic characteristics. The molecular and genetic heterogeneity of B-NHLs may contribute to the poor outcome of some of these diseases, suggesting that more personalized precision-medicine approaches are needed for improved therapeutic efficacy. The germinal center (GC) B-cell like diffuse large B-cell lymphomas (GCB-DLBCLs) and follicular lymphomas (FLs) share specific epigenetic programs. These diseases often remain difficult to treat and surprisingly do not respond advanced immunotherapies, despite arising in secondary lymphoid organs at sites of antigen recognition. Epigenetic dysregulation is a hallmark of GCB-DLBCLs and FLs, with gain-of-function (GOF) mutations in the histone methyltransferase EZH2, loss-of-function (LOF) mutations in histone acetyl transferases CREBBP and EP300, and the histone methyltransferase KMT2D representing the most prevalent genetic lesions driving these diseases. These mutations have the common effect to disrupt the interactions between lymphoma cells and the immune microenvironment, via decreased antigen presentation and responsiveness to IFN-γ and CD40 signaling pathways. This indicates that immune evasion is a key step in GC B-cell lymphomagenesis. EZH2 inhibitors are now approved for the treatment of FL and selective HDAC3 inhibitors counteracting the effects of CREBBP LOF mutations are under development. These treatments can help restore the immune control of GCB lymphomas, and may represent optimal candidate agents for more effective combination with immunotherapies. Here, we review recent progress in understanding the impact of mutant chromatin modifiers on immune evasion in GCB lymphomas. We provide new insights on how the epigenetic program of these diseases may be regulated at the level of metabolism, discussing the role of metabolic intermediates as cofactors of epigenetic enzymes. In addition, lymphoma metabolic adaptation can negatively influence the immune microenvironment, further contributing to the development of immune cold tumors, poorly infiltrated by effector immune cells. Based on these findings, we discuss relevant candidate epigenetic/metabolic/immune targets for rational combination therapies to investigate as more effective precision-medicine approaches for GCB lymphomas.

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“…Patients with a history of headache before treatment may be more susceptible to headache following treatment [ 31 – 34 ]. Patients may suffer from headaches during or shortly after the first infusion of cetuximab [ 33 , 35 ], bevacizumab [ 36 ], ipilimumab [ 32 ], rituximab [ 37 ], chimeric antigen receptor T cells (CAR-T) [ 21 ], and pembrolizumab [ 38 ] ( Table 1 ). The symptoms are mostly self-limited, persisting for several days and decreasing soon after finishing the treatment [ 18 , 39 ].…”

Section: Neurotoxic Features Of Immunotherapymentioning

confidence: 99%

Neurotoxicity of Tumor Immunotherapy: The Emergence of Clinical Attention

Zhang

Xue

Yin

et al. 2022

Journal of Oncology

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Tumor immunotherapy brings substantial and long-term clinical benefits that can even cure tumors. However, the accumulation of evidence suggests that immunotherapy also induces severe and complex neurologic immune-related adverse events (ir-AEs) and even leads to immunotherapy-related death, which arouses the concern of clinicians. The timely and accurate identification of neurotoxicity helps clinicians detect and treat these complications early, thereby enhancing treatment efficiency and improving the prognosis of patients. At present, the mechanism of neurotoxicity caused by immunotherapy has not been completely elucidated. This paper mainly reviews the clinical features, pathogenesis, and therapeutic strategies of neurologic ir-AEs.

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Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial

Cited by 99 publications

References 26 publications

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer

Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies

Neurotoxicity of Tumor Immunotherapy: The Emergence of Clinical Attention

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