SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy

Abstract

Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion-positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion-positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit.

Significance: PF-07284892-targeted therapy combinations overcame bypass-signaling-mediated resistance in a clinical setting in which neither component was active on its own. This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development. See related commentary by Hernando-Calvo and Garralda, p. 1762. This article is highlighted in the In This Issue feature, p. 1749.

Figure 1.

PF-07284892 promotes antitumor efficacy in multiple oncogene-addicted models with up-front or acquired resistance to targeted therapies. A, X-ray crystal structure of PF-07284892–bound SHP2. N-SH2, C-SH2, and PTP domains are yellow, cyan, and violet; inhibitor is green/blue. See Supplementary Table S1 for data collection and refinement statistics. B–D, Top, the indicated human cancer cell lines were treated in vitro with each agent at the indicated concentrations for 4 (H3122 lorR-06), 18 (VACO-432), or 24 (MIA PaCa-2) hours followed by preparation of cell lysates and analysis of the indicated protein by immunoblot. Quantitation of each band is shown in Supplementary Fig. S3. Bottom, immunodeficient mice (8 per group) were xenografted subcutaneously with the same human tumor cells used for in vitro signaling analysis. When tumors reached ∼200 mm³, animals were treated orally with vehicle, PF-07284892 30 mg/kg q.o.d., lorlatinib 3 mg/kg qd, encorafenib 20 mg/kg qd + binimetinib 3.5 mg/kg b.i.d., binimetinib 3.5 mg/kg b.i.d., or with the indicated combinations (at the monotherapy doses). Tumor sizes on days 25 to 29 were normalized to day 1 prior to treatment. b.i.d., twice daily; Bini, binimetinib; C, carboxy-proximal; CRC, colorectal cancer; Enco, encorafenib; Lorla, lorlatinib; N, amino-proximal; NSCLC, non–small cell lung cancer; p, phosphorylated; PDAC, pancreatic ductal adenocarcinoma; PTP, phosphatase; qd, daily; q.o.d., every other day; t, total.

Figure 2.

Proof-of-concept clinical activity in an ALK fusion–positive NSCLC patient with resistance to multiple ALK inhibitors. A, Overview of traditional vs. alternative phase I combination trial design. Left, traditional phase I first-in-human trials require a new anticancer agent to be investigated as monotherapy, with the maximum tolerated dose/recommended dose for expansion identified, prior to allowing a combination with a second anticancer drug. If the investigational agent is ineffective on its own, treated patients do not have the opportunity to benefit from a potentially efficacious combination. Right, an alternative design allows patients to receive treatment with a potentially effective combination after an initial period of treatment with the study drug as monotherapy. B, Implementation of early combination testing strategy with the investigational SHP2 inhibitor PF-07284892. Prior to trial enrollment, eligible patients had experienced PD with appropriate targeted therapy. Patients begin treatment with PF-07284892 monotherapy on study. Early combination with appropriate targeted therapy (lorlatinib, encorafenib + cetuximab, or binimetinib, each at the approved dose) may be initiated after a minimum of 6 weeks of PF-07284892 monotherapy, in the absence of ongoing grade ≥3 toxicity or DLT, and after PD (symptoms of PD without tumor growth ≥20% was allowed). At the start of the combination, the PF-07284892 dose must be lowered if the monotherapy dose level the patient was enrolled to has not yet been cleared from a safety perspective. The dose may subsequently be escalated to the highest monotherapy dose that has been cleared. C, The patient's previous systemic therapies included four approved ALK inhibitors. Parentheses show the best overall response to each treatment. D, Peripheral blood was isolated from the patient prior to and 4 hours after dosing with PF-07284892 on C1D1 and C1D18, and levels of PF-07284892 in plasma and of pERK in ex vivo CSF1-stimulated peripheral blood monocytes were analyzed (C1D18 samples for pERK were not available). The last dose of PF-07284892 prior to the C1D18 predose sampling was C1D15. The horizontal dashed line indicates PF-07284892 concentration required to inhibit 50% of pERK in cells in vitro. E, Changes in the sum of the longest tumor diameters of target lesions (blue, normalized to the start of combination) and in EML4–ALK, ALK–EML4, ALK^G1202R (shades of green), and ALK^G1269A (red) in ctDNA. C, cycle; Cp, plasma concentration; CRC, colorectal cancer; ctDNA, circulating tumor DNA; D, day; DL, dose level; MAF, mean allele frequency; NA, not available; PD, progressive disease; pERK, phosphorylated ERK; PF-4892, PF-07284892; PK/PD, pharmacokinetics/pharmacodynamics; POC, percent of control; PR, partial response; qd, every day.

Figure 3.

PF-07284892 overcomes intrinsic resistance to encorafenib + cetuximab in a BRAF^V600E-mutant CRC patient. A, The patient's previous systemic therapies were chemotherapy + bevacizumab, encorafenib + cetuximab, and fruquintinib, with the best overall response PD, indicating primary progression/intrinsic resistance to each therapy. B, Levels of PF-07284892 (red squares) in plasma, as in Fig. 2D; blood samples for pERK were not available. C, Change in the sum of the longest tumor diameters of target lesions and in BRAF^V600E (and other mutations) in ctDNA over time, as in Fig. 2E. D, Imaging of a right-sided intra-abdominal target lesion mass during study treatment. The patient experienced one AE with monotherapy (grade 2 ascites not related to study treatment) and three grade 1 AEs with combination treatment (headache, fatigue, and acneiform rash, the latter a known toxicity of cetuximab). bev, bevacizumab; b.i.d., twice daily; C, cycle; cetux, cetuximab; Cp, plasma concentration; CRC, colorectal cancer; D, day; enco, encorafenib; FOLFIRI, folinic acid, fluorouracil, irinotecan; FOLFOX, folinic acid, fluorouracil, oxaliplatin; MAF, mean allele frequency; PD, progressive disease; PF-4892, PF-07284892; SD, stable disease; uPR, unconfirmed partial response.

Figure 4.

PF-07284892 sensitizes a patient with KRAS^G12D-mutant ovarian cancer to the MAPK pathway inhibitor binimetinib. A, Prior treatments for metastatic disease included ASN-007 (investigational ERK inhibitor), chemotherapy, niraparib, and SGN-STNV (investigational antibody–drug conjugate). B, Levels of PF-07284892 in plasma (red squares) and pERK in ex vivo CSF1-stimulated peripheral blood monocytes (blue bars), as in Fig. 2D. C, Change in the sum of the longest tumor diameters of target lesions and of ATM^L1517P in ctDNA over time, as in Fig. 2E. D, Imaging of two abdominal target lesions during study treatment. All treatment-related AEs were grade 1 except for edema (grades 1–2, starting on monotherapy, worsening on the combination, and leading to dose modification), fatigue (grades 2–3), weight gain, diarrhea, and eczema (each grade 2 and resolved by the end of treatment). ADC, antibody–drug conjugate; b.i.d., twice daily; bini, binimetinib; C, cycle; Cp, plasma concentration; D, day; ERKi, ERK inhibitor; MAF, mean allele frequency; NA, not available; PD, progressive disease; PF-4892, PF-07284892; POC, percentage of control.