Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors

Shapiro, Geoffrey I.; LoRusso, Patricia; Kwak, Eunice L.; Pandya, Susan S.; Rudin, Charles M.; Kurkjian, Carla; Cleary, James M.; Pilat, Mary Jo; Jones, Suzanne F.; Crespigny, Alex de; Fredrickson, Jill; Musib, Luna; Yan, Yibing; Wongchenko, Matthew J.; Hsieh, Hsin‐Ju; Gates, Mary; Chan, Iris T.; Bendell, Johanna C.

doi:10.1007/s10637-019-00776-6

Cited by 61 publications

(43 citation statements)

References 32 publications

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“…No objective responses were observed, consistent with the inadequate efficacy reported from studies with other PI3K and MEK inhibitor combinations [ 25 , 26 , 28 – 30 ]. This was unexpected based on preclinical evidence of such combinations being synergistic [ 3 , 4 ].…”

Section: Discussionsupporting

confidence: 76%

Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer

et al. 2020

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Background Dual inhibition of PI3K and MAPK signaling is conceptually a promising anticancer therapy. Objective This phase 1b trial investigated the safety, maximum tolerated dose (MTD), recommended phase II dose, pharmacokinetics, tumor response, fluorodeoxyglucose positron emission tomography (FDG-PET) pharmacodynamics, and biomarker explorations for the combination of pan-PI3K inhibitor copanlisib and allosteric MEK inhibitor refametinib in patients with advanced solid tumors. Patients and methods This was an adaptive trial with eight dose cohorts combining dose escalation and varying schedules in repeated 28-day cycles. Patients received copanlisib (0.2–0.8 mg/kg intravenously) intermittently (days 1, 8, 15) or weekly (days 1, 8, 15, 22) each cycle, and refametinib (30–50 mg twice daily orally) continuously or 4 days on/3 days off. Patients with KRAS , NRAS , BRAF , or PI3KCA mutations were eligible for the expansion cohort. Results In the dose-escalation ( n = 49) and expansion ( n = 15) cohorts, the most common treatment-emergent adverse events included diarrhea (59.4%), nausea, acneiform rash, and fatigue (51.6% each). Dose-limiting toxicities included oral mucositis ( n = 4), increased alanine aminotransferase/aspartate aminotransferase ( n = 3), acneiform rash, hypertension ( n = 2 each), and diarrhea ( n = 1). MTD was copanlisib 0.4 mg/kg weekly and refametinib 30 mg twice daily. No pharmacokinetic interactions were identified. Decreased tumor FDG uptake and MEK-ERK signaling inhibition were demonstrated during treatment. Best response was stable disease ( n = 21); median treatment duration was 6 weeks. Conclusions Despite sound rationale and demonstrable pharmacodynamic tumor activity in relevant tumor populations, a dose and schedule could not be identified for this drug combination that were both tolerable and offered clear efficacy in the population assessed. Clinicaltrials.gov identifier NCT01392521. Electronic supplementary material The online version of this article (10.1007/s11523-020-00714-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 76%

Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer

et al. 2020

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“…These inhibitors can be used to treat certain cancers but feedback mechanisms leading to the activation of other effector pathways and a narrow therapeutic window have meant that their efficacy in Ras-mutant cancers is limited (12). Combination trials to assess the efficacy of blocking components from both pathways are currently underway (13)(14)(15)(16), however preliminary results have suggested that these combinations are too toxic (17,18).…”

Section: Downloaded Frommentioning

confidence: 99%

“…The constructs expressing RalA (pMAT10, residues 1-184, Q72L) (36), RalB (pMAT10, 1-185, Q72L) (36), RLIP76 RBD (pGEX-HisP, 393-446, C411S) (54), RhoA (pGEX-2T, 1-186, F25N/Q63L) (55), Rac1 (pGEX-2T, 1-185, Q61L) (56), Cdc42 (pGEX-2T, 1-184, Q61L) (56) and K-Ras (pGEX-6P, 1-169) (38) were prepared, expressed and cleaved from their tags as described previously. 15 N-labeled RalB (1-185, Q72L) was prepared from pET16b in M9 minimal media supplemented with 15 NH4Cl as described previously (36), without cleaving the His-tag.…”

Section: Protein Preparationmentioning

confidence: 99%

Affinity maturation of the RLIP76 Ral binding domain to inform the design of stapled peptides targeting the Ral GTPases

Hurd

Brear

Revell

et al. 2021

Journal of Biological Chemistry

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Ral GTPases have been implicated as critical drivers of cell growth and metastasis in numerous Ras-driven cancers. We have previously reported stapled peptides, based on the Ral effector RLIP76, that can disrupt Ral signaling. Stapled peptides are short peptides that are locked into their bioactive form using a synthetic brace. Here, using an affinity maturation of the RLIP76 Ral-binding domain, we identified several sequence substitutions that together improve binding to Ral proteins by more than 20-fold. Hits from the selection were rigorously analyzed to determine the contributions of individual residues and two 1.5 Å co-crystal structures of the tightest-binding mutants in complex with RalB revealed key interactions. Insights gained from this maturation were used to design second-generation stapled peptides based on RLIP76 that exhibited vastly improved selectivity for Ral GTPases when compared to the first-generation lead peptide. The binding of second-generation peptides to Ral proteins was quantified and the binding site of the lead peptide on RalB was determined by NMR. Stapled peptides successfully competed with multiple Ral-effector interactions in cellular lysates. Our findings demonstrate how manipulation of a native binding partner can assist in the rational design of stapled peptide inhibitors targeting a protein–protein interaction.

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“…Accordingly, MEK/ERK has also been proposed as a potential target for therapy ( Table 1). Several MEK inhibitors have been reported including Trametinib [35], Cobimetinib [36], Binimetinib [37], Selumetinib [38], some of these have been investigated in clinical trials. Specifically, Trametinib has been used with 4-1BB and OX40 agonists to enhance T-cell costimulation [19].…”

Section: Mek/erk Inhibitionmentioning

confidence: 99%

Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

et al. 2020

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Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several components of the MAPK signaling network have been proposed as viable targets for cancer therapy. However, the contributions of MAPK signaling extend well beyond the tumor cells, and several MAPK effectors have been identified as key mediators of the tumor microenvironment (TME), particularly with respect to the local immune infiltrate. In fact, a blockade of various MAPK signals has been suggested to fundamentally alter the interaction between tumor cells and T lymphocytes and have been suggested a potential adjuvant to immune checkpoint inhibition in the clinic. Therefore, in this review article, we discuss the various mechanisms through which MAPK family members contribute to T-cell biology, as well as circumstances in which MAPK inhibition may potentiate or limit cancer immunotherapy.

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Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors

Cited by 61 publications

References 32 publications

Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer

Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer

Affinity maturation of the RLIP76 Ral binding domain to inform the design of stapled peptides targeting the Ral GTPases

Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

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