batoprotafib (TNO155)

P1, N=122, Terminated, Novartis Pharmaceuticals | Trial completion date: Jan 2025 --> Sep 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2025 --> Sep 2024; The decision of early termination was made due to business reasons, and was not based on any safety concerns for any of the treatment combinations.

P1/2, N=344, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | Trial completion date: Jan 2027 --> Mar 2026 | Trial primary completion date: Jan 2027 --> Mar 2026

P1, N=1200, Recruiting, Amgen | Trial completion date: Jun 2029 --> Mar 2028 | Trial primary completion date: Jan 2027 --> Apr 2026

P1, N=1200, Recruiting, Amgen | Trial completion date: Mar 2028 --> Jun 2029 | Trial primary completion date: Sep 2025 --> Jan 2027

P1, N=122, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2024 --> Jan 2025 | Trial primary completion date: Oct 2024 --> Jan 2025

In this study, we demonstrated that MEST inhibited IFN-γ secretion from CD8+ T cells by up-regulating SHP2, thereby downregulating MHCI expression in GC cells to promote immune escape and providing a new T cell-based therapeutic potential for GC.

P1, N=86, Active, not recruiting, Mirati Therapeutics Inc. | Phase classification: P1/2 --> P1

P1, N=1200, Recruiting, Amgen | Trial primary completion date: Dec 2026 --> Sep 2025

P1, N=227, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

P1/2, N=86, Active, not recruiting, Mirati Therapeutics Inc. | Trial completion date: Mar 2024 --> Dec 2024

P1, N=1200, Recruiting, Amgen | Phase classification: P1/2 --> P1

P1/2, N=1126, Recruiting, Amgen | Trial primary completion date: Sep 2026 --> Dec 2026

P1, N=0, Withdrawn, Novartis Pharmaceuticals | N=48 --> 0 | Trial completion date: Jun 2024 --> Jul 2025 | Not yet recruiting --> Withdrawn | Trial primary completion date: Jun 2024 --> Jul 2025

P1, N=0, Withdrawn, Novartis Pharmaceuticals | N=48 --> 0 | Trial completion date: Jun 2024 --> Jun 2025 | Not yet recruiting --> Withdrawn | Trial primary completion date: Jun 2024 --> Jun 2025

P1, N=122, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: May 2024 --> Sep 2024 | Trial primary completion date: May 2024 --> Sep 2024

P1, N=122, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Business reasons

P1, N=255, Recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2024 --> Apr 2025 | Trial primary completion date: Oct 2024 --> Apr 2025

JDQ443 demonstrates an acceptable safety and tolerability profile at 200 mg BID, with clinical activity in pts with NSCLC. Enrollment is ongoing to the JDQ443 monotherapy DEx and the JDQ443 + TNO155 and JDQ443 + tislelizumab combination arms.

P1/2, N=1143, Recruiting, Amgen | Trial primary completion date: Jun 2026 --> Sep 2026

In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its antiproliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.

P1/2, N=1143, Recruiting, Amgen | Phase classification: P1b/2 --> P1/2

To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the CDK4/6 inhibitor ribociclib, in xenograft models derived from a KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition. Overall, KRAS G12C amplification and alterations of the MAPK/PI3K pathway were predominant mechanisms of resistance to combined KRASG12C/SHP2 inhibitors in preclinical settings. The biological nodes identified by CRISPR screening might provide additional starting points for effective combination treatments.

Our group showed a selective response (~40%) with the PD-1 blocking antibody pembrolizumab in patients with RT, particularly after prior exposure to ibrutinib (Ding et al, Blood, 2017)...SHP-1 (TPI-1) and SHP-1+SHP-2 (TPI-1+TNO155) inhibitor treatment promoted OCI-LY19 cell death and led to recovery of phosphorylation on ATM, Chk-2 and p53 in these cells... Our data showed robust PD-1 expression in patients with Richter transformation from CLL to DLBCL. PD-1 overexpression in DLBCL lymphoma cell lines enhanced cell proliferation in vitro and in vivo. Further investigation identified that PD-1 modified the phosphorylation/function of SHP phosphatases and thereby regulated p53 pathways (Figure 1).

P1b/2, N=1143, Recruiting, Amgen | Trial completion date: Jul 2027 --> Oct 2027

JDQ443 demonstrates an acceptable safety and tolerability profile at 200 mg BID, with clinical activity in NSCLC pts. Enrollment is ongoing to the JDQ443 monotherapy DEx and the JDQ443+TNO155 and JDQ443+tislelizumab arms.

We report on the generation of MPN BM in an ex vivo bioreactor system with Jak2V617F stem/progenitors engrafting into engineered niches and recapitulating MPN. We observed that SHP2 inhibition with TNO155 had differential effects to ruxolitinib primarily affecting LSK and erythroid compartments, which suggests a translational potential of dual JAK2/SHP2 inhibition in MPN. A humanized bioreactor system engineered from primary MPN patient cells is being setup.

To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine-threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components...Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic.

P1/2, N=86, Active, not recruiting, Mirati Therapeutics Inc. | Trial completion date: Oct 2023 --> Mar 2024 | Trial primary completion date: Sep 2022 --> Mar 2024

P1b/2, N=1143, Recruiting, Amgen | Trial primary completion date: Jan 2025 --> May 2026

P1b/2, N=1143, Recruiting, Amgen | Trial completion date: Jan 2029 --> Jul 2027 | Trial primary completion date: Jul 2026 --> Jan 2025

JDQ443+TNO155 was tolerated with notable toxicities of edema, cytopenias, and fatigue. MTD was not reached; the RD for further evaluation was selected based on collective safety, pharmacokinetics, and efficacy. Preliminary anti-tumor activity was observed, including in KRASG12C inhibitor previously-treated NSCLC.

P1, N=255, Recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2024 --> Aug 2024 | Trial primary completion date: Feb 2024 --> Aug 2024

P1/2, N=475, Recruiting, Novartis Pharmaceuticals | Trial completion date: May 2025 --> Jan 2027 | Trial primary completion date: May 2025 --> Jan 2027

P1, N=122, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=350 --> 122

Pharmacologic targeting by SHP2 inhibitors TNO155 or IACS-13909 as well as dual SHP2/JAK2 targeting was evaluated in MPN cell lines and primary MPN patient cells. Our findings suggest a relevant role of SHP2 in MPN given enhanced MAPK pathway suppression and correctiveeffects when SHP2 is targeted in MPN cells, mouse models and primary patient isolates. Further studies will delineate the involvement of SHP2 phosphatase vs. non-phosphatase functions and detail the potential of JAK2/SHP2 inhibition as therapeutic approach in MPN.

JDQ443 demonstrates an acceptable safety and tolerability profile at 200 mg BID, with clinical activity in pts with NSCLC. Enrollment is ongoing to the JDQ443 monotherapy DEx and the JDQ443 + TNO155 and JDQ443 + tislelizumab combination arms. Clinical trial information: NCT04699188.

P1, N=350, Recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2024 --> Apr 2024 | Trial primary completion date: Oct 2024 --> Apr 2024

P1, N=122, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=185 --> 122 | Trial completion date: Apr 2025 --> Oct 2023 | Trial primary completion date: Apr 2025 --> Oct 2023

P1b/2, N=1143, Recruiting, Amgen | Trial completion date: Apr 2028 --> Jan 2029 | Trial primary completion date: Feb 2026 --> Jul 2026

A set of immuno-oncology reagents, including anti-PD-1/L1, CSF-1R inhibitor (ABSK021) and CD73 inhibitor (ABSK051) were also tested in combination with ABSK071 in vivo using mouse syngeneic models. ABSK071 demonstrated much stronger inhibitory activity than sotorasib and adagrasib against a variety of cell lines harboring KRASG12C, as well as significantly better in vivo anti-tumor efficacy in xenograft models that were less sensitive to sotorasib. Synergistic effects on cell growth inhibition were observed in vitro with ABSK071 in combination with several agents including cetuximab, afatinib, AZD4547, TNO-155, RMC-4630 and BI3406... ABSK071 is a next-generation KRASG12C inhibitor with greater activity and anti-tumor efficacy in vitro and in vivo. It also demonstrated broad synergistic effects with a large set of targeted agents and immuno-oncology agents, indicating its strong potential in combinatory therapy in treating a wider range of KRASG12C-dependent cancers.

P1/2, N=86, Active, not recruiting, Mirati Therapeutics Inc. | Trial completion date: Oct 2022 --> Oct 2023

P1b/2, N=1143, Recruiting, Amgen | Trial completion date: Jun 2027 --> Apr 2028 | Trial primary completion date: Dec 2024 --> Feb 2026