Background

Oncogene-dependency is an important therapeutic principle. Fibroblast growth factor receptors (FGFR) alterations include amplification (amp), fusion (fus) and mutation (mut) and are found in several cancer types. Which alterations truly lead to the clinical efficacy of FGFR inhibitors need to be clarified.

Methods

We retrospectively assessed data from patients treated with pan-FGRF inhibitors in phase I/II trials at Gustave Roussy Institut including JnJ-42756493, BGJ-398, INCB-54828-202 and TAS-120 between February 2011 and June 2020.

Results

Among 92 patients 22 had a FGFR amp, 33 a FGFR fus and 37 a FGFR mut. Patients with an amp were younger (43 median age, p=0.02) and patients with a mut were older (60.5 median age, p=0.03) compared to patients with other FGFR alterations. Most frequent tumor types were urothelial cancer (23.9%), cholangiocarcinoma (21.7%), breast cancer (20.7%) and central nervous system cancer (13%). Best response rates according to alteration are listed in the table. Patients with an amp had a shorter progression free survival (PFS) compared to other alterations with a median of 2.23 months (mo) vs 5.23 mo (HR=2.64, 95% CI[1.55-4.51], p<0.01). Patients with a fus had a longer PFS than other alterations with a median of 6.20 mo vs 2.70 mo (HR=0.61, 95% CI[0.38-0.98], p=0.04). Patients with a mut had a similar PFS compared to other alterations with a median of 2.77 mo vs 3.67 mo (HR=0.91, 95% CI[0.57-1.44], p=0.70). No significant difference in overall survival was found. Table: 34MO

Best response rate according to FGFR alteration

Conclusions

The clinical benefit of FGFR inhibition is stronger in case of FGFR fus or mut compared to FGFR amp. The role of pan-FGFR inhibitors in amplified tumors remains unclear and requires further investigation.

Clinical trial identification

JnJ-42756493 (NCT01703481) published in 2019 May; 14 BGJ-398 (NCT01004224) published in 2016 November; 21 TAS-120 (NCT02052778) published in 2020 July; 2 INCB-54828-202 (NCT02924376) published July 7.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

C.J. Pobel: Travel/Accommodation/Expenses: Amgen, Sandoz. L. Verlingue: Honoraria (self), LV reports personal fees from Adaptherapy, outside of the submitted work: Adaptherapy. J-C. Soria: Advisory/Consultancy: AbbVie, AstraZeneca, Bayer, Blend Therapeutics, Boehringer Ingelheim, Cytomix, Daiichi, Eli Lilly, Genmab, Guardant, Inivata, Merck, Netcancer, PharmaMar, Roche, Servier, Tarveda; Leadership role, Full/Part-time employment, Senior vice president AstraZeneca 09/2017-12/2019: AstraZeneca; Leadership role, Full/Part-time employment, Directeur general since 01/2020: Institut Gustave Roussy. L. Friboulet: Research grant/Funding (institution), research funding FGFR TKI: Incyte, Debiopharm. All other authors have declared no conflicts of interest.

Background

Targeting FGFR genetic alterations using small molecule inhibitors is a validated therapeutic strategy for urothelial carcinoma and cholangiocarcinoma. However, the current FDA-approved pan-FGFR inhibitors, erdafitinib and pemigatinib, are subject to FGFR1-mediated dose-limiting toxicities (e.g., hyperphosphatemia). These treatments necessitate a high rate of dose reductions, interruptions, and discontinuations, thereby potentially limiting efficacy. In addition, drug-resistant mutations (e.g., gatekeeper) in FGFR2 and FGFR3 genes rapidly emerge in patients treated with these drugs. Our research goals are to reveal the full spectrum of oncogenic FGFR2 and FGFR3 mutations that drive tumor growth and to discover an inhibitor that selectively targets these mutations together with FGFR2 and FGFR3 gene fusion and drug-resistance mutations, while minimizing FGFR1 activity and associated toxicities. We hypothesize that this will deliver an FGFR precision medicine with enhanced anti-tumor activity, an improved drug resistance profile, and broader mutational coverage.

Methods

Applying the Mutation-Allostery-Pharmacology (MAP) platform technology developed by Black Diamond Therapeutics, we define a spectrum of 20 allosteric FGFR2/3 oncogenic mutations, including 10 previously uncharacterized mutations that we now show to be oncogenic. We demonstrated how this mutation family is activated due to disulfide-bond mediated dimerization; hence we term these mutations locked-dimer (Lo-Di) FGFR oncogenes.

Results

Herein, we report the discovery of a series of orally available, selective Lo-Di-FGFR2/3 inhibitors that 1) shows antiproliferative potency across all 20 mutations; 2) spares FGFR1-wild-type; 3) is active against gatekeeper mutations and 4) shows favorable selectivity versus a subset of closely related kinases in the human kinome. When dosed orally, one example was well tolerated and exhibited dose-dependent PK/PD and anti-tumor efficacy and regression in the UM-UC-14 xenograft model in mice.

Conclusions

Our data support the development of rationally designed selective inhibitors targeting a spectrum of FGFR2/3 mutations while sparing dose limiting FGFR1 activity.

Legal entity responsible for the study

Black Diamond Therapeutics.

Funding

Black Diamond Therapeutics.

Disclosure

E. Dardenne, F. Padilla, S. Rasmussen, S.N. Yang, A. Mentes, L.S. Ogawa, R. Fiorenza, A. Trombino, S. Smith, D. Romashko, N. Ishiyama, M. Chevtsova, S. Thakur, E. Rosfjord, E. Buck, C. Roberts, M. Lucas, T-A. Lin: Shareholder/Stockholder/Stock options, Full/Part-time employment: BDTX.

Background

Effective treatment of patients with metastatic non-small cell lung cancer (mNSCLC) harboring EGFR or HER2 exon 20 insertion mutations represents a critical unmet need. Poziotinib is a potent, irreversible, tyrosine kinase inhibitor (TKI) being studied in a multi-cohort phase II study (ZENITH20). Poziotinib half-life of 7.2 hours and pharmacokinetic modeling suggests an opportunity to improve tolerability with a twice daily (BID) dosing schedule. Here we present efficacy data from once daily (QD) in treatment naïve patients as well as an exploratory study of BID dosing.

Methods

ZENITH20-3 enrolled treatment-naïve mNSCLC patients with EGFR exon 20 mutations at 16mg QD. Patients were treated until death, progression or significant toxicity. ZENITH20-5 treated patients with EGFR or HER2 exon 20 mutations in randomized arms of 10, 12, 16 mg QD or 6 and 8 mg BID. The endpoints were objective response rate (ORR per RECIST 1.1), duration of response (DOR), progression-free-survival (PFS) and safety.

Results

In ZENITH20-3 (N=79), the median time of follow up was 9.2 months with 12 patients still receiving treatment. The intent-to-treat analysis showed an ORR of 27.8% (22/79; 95% CI: 18.4 – 39.1%) and disease control rate of 86.1%. 91% of all study patients had tumor reduction. The median DOR was 6.5 months and the median PFS was 7.2 months. Adverse event profile was similar to 2^nd generation EGFR TKIs with ≥ grade 3 rash of 33% and diarrhea of 23%. Preliminary data from ZENITH20-5 (N=40) randomized cohorts of QD vs BID dosing (16mg QD vs 8mg BID; 12mg QD vs and 6mg BID) indicate that the expected AE rate was lower with BID dosing (31% vs. 21% and 27% vs. 16% respectively) in cycle 1. BID dosing schedules resulted in the relative reduction in dose interruptions by 38% and 52% respectively. Updated safety, tolerability and preliminary efficacy data will be presented.

Conclusions

Poziotinib demonstrated clinically meaningful activity in treatment-naïve mNSCLC patients with EGFR exon 20 mutations at 16 mg QD dosing. Preliminary data demonstrates improved tolerability and safety with BID dosing strategy and warrants further evaluation.

Clinical trial identification

NCT03318939.

Legal entity responsible for the study

Spectrum Pharmaceuticals, Inc.

Funding

Spectrum Pharmaceuticals, Inc.

Disclosure

A. Sacher: Honoraria (institution), Advisory/Consultancy: AstraZeneca; Honoraria (institution), Advisory/Consultancy: Amgen; Honoraria (institution), Advisory/Consultancy: Merck; Honoraria (institution): Pfizer; Honoraria (institution), Advisory/Consultancy: Bayer; Honoraria (institution), Advisory/Consultancy: Genentech-Roche; Honoraria (institution), Advisory/Consultancy: Kisoji; Honoraria (institution), Advisory/Consultancy: BMS; Honoraria (institution): Tesaro. X. Le, M. Socinski, M.C. Garassino: Research grant/Funding (institution): Spectrum Pharmaceuticals. J. Clarke: Advisory/Consultancy: Spectrum Pharmaceuticals. G. Bhat, F. Lebel: Full/Part-time employment: Spectrum Pharmaceuticals. All other authors have declared no conflicts of interest.

Background

CC-90010, a potent oral BETi, was well-tolerated with promising activity in pts with advanced malignancies. We present longer follow-up results of parts A (A) and B (B) from CC-90010-ST-001 and, for the first time, results from part C (C) describing food effect on CC-90010 pharmacokinetics (PK).

Methods

CC-90010-ST-001 is a phase I dose-escalation (A) and -expansion (B) study of CC-90010 in pts with aSTs and R/R DLBCL also evaluating high-calorie/-fat meal effects on CC-90010 PK in pts with aSTs (C); 11 dose levels (DLs) and 4 schedules (2 weekly [2 d on/5 d off; 3 d on/4 d off], 1 biweekly [3 d on/11 d off] and 1 monthly [4 d on/24 d off]) were tested. Primary objectives were safety, tolerability, maximum tolerated dose and recommended phase II dose (RP2D). Secondary and exploratory objectives were antitumor activity, PK, pharmacodynamics and food effect.

Results

As of 3 Nov 2020, 133 pts were enrolled. In A and B, 67 and 2 pts had aSTs; 2 and 21 pts had R/R DLBCL. In C, 41 pts had aSTs. In A, 6 pts (11%) had dose-limiting toxicities across dosing schedules. The most common grade 3/4 treatment-related adverse event (TRAE) was thrombocytopenia (A, 16%; B, 76%; C, 10%); 8 pts (12%) in A, 6 (29%) in B, and 2 (5%) in C had serious TRAEs. In A, 1 pt (progressing grade 2 astrocytoma) had a complete response (CR) before progression (19 cycles); 1 pt (endometrial carcinoma) had a partial response (PR; 8 cycles). In B, 2 pts with R/R DLBCL responded (CR, PR). In C, 2 pts (parotid basal cell adenocarcinoma, nasopharyngeal cancer) had durable PRs, and 23 had stable disease (≥4 mo in 9 pts); 1 pt (relapsing glioblastoma) had a minor response. Plasma exposures rose dose-proportionally across DLs. CC-90010 terminal half-life was ∼60 h and PK was similar under fasted vs fed conditions in C. CC-90010 ≥25 mg caused ≥50% decrease in CCR1 mRNA (BETi blood biomarker) 4 h after last dose. CCR1 modulation was similar in A and B after first and last dose at the RP2D.

Conclusions

Overall, CC-90010 was very well tolerated with promising antitumor activity and PK not impacted by food intake, supporting exploration in combination therapy.

Clinical trial identification

NCT03220347; EUDRACT 2015-004371-79.

Editorial acknowledgement

Writing and editorial assistance were provided by Brittany L. Phillips, PhD, of Bio Connections LLC, funded by Bristol Myers Squibb Company.

Legal entity responsible for the study

Celgene, a Bristol-Myers Squibb Company.

Funding

Celgene, a Bristol-Myers Squibb Company.

Disclosure

V. Moreno: Advisory/Consultancy: BMS; Advisory/Consultancy: Bayer; Advisory/Consultancy: Pieris; Advisory/Consultancy: Janssen. M. Vieito Villar: Advisory/Consultancy: Debio; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: TFS; Travel/Accommodation/Expenses: Merck-Serono. J.M. Sepulveda Sanchez: Speaker Bureau/Expert testimony: Astellas; Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy, Travel/Accommodation/Expenses: AbbVie; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Celgene, a Bristol-Myers Squibb Company; Advisory/Consultancy: GW Pharma. O. Saavedra: Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Kyowakirin. C. Carlo Stella: Honoraria (self), Speaker Bureau/Expert testimony: MDS; Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self): BMS; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): ADCT; Advisory/Consultancy: Sanofi; Research grant/Funding (institution): Novartis; Travel/Accommodation/Expenses: Takeda; Honoraria (self), Travel/Accommodation/Expenses: Janssen. J-M. Michot: Honoraria (self): Celgene; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): AstraZeneca; Honoraria (self): Janssen. A. Italiano: Advisory/Consultancy, Research grant/Funding (self): Bayer; Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy: Springworks; Advisory/Consultancy: Epizyme; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Merck; Research grant/Funding (self): MSD; Research grant/Funding (self): PharmaMar. M. Magagnoli: Honoraria (self): Sanofi; Honoraria (self): AstraZeneca. C. Carpio: Advisory/Consultancy: Regeneron; Advisory/Consultancy, Travel/Accommodation/Expenses: Takeda; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Gilead; Travel/Accommodation/Expenses: Sandoz; Travel/Accommodation/Expenses: Celgene. R. Sarmiento: Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, a Bristol-Myers Squibb Company. B. Amoroso: Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene. I. Aronchik: Shareholder/Stockholder/Stock options, Full/Part-time employment: BMS. E. Filvaroff: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: BMS; Shareholder/Stockholder/Stock options: Amgen; Shareholder/Stockholder/Stock options: Gilead; Shareholder/Stockholder/Stock options: Genentech/Roche. B. Hanna: Research grant/Funding (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: BMS. A. Pinto: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self): Celgene; Honoraria (self): Servier; Honoraria (self): BMS; Honoraria (self): MSD; Advisory/Consultancy: Novartis; Travel/Accommodation/Expenses: Takeda. Z. Nikolova: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, a Bristol-Myers Squibb Company. I. Braña: Research grant/Funding (self): Celgene, a Bristol-Myers Squibb Company. All other authors have declared no conflicts of interest.

Background

STK11 and KEAP1 loss are strongly co-associated (p<0.001) in lung adenocarcinoma (LUAD). Our team has found that in a 468-gene panel, co-occurrence of these two mutations is the strongest driver of poor outcome in LUADs, conferring resistance to both standard chemotherapy and immunotherapy, resulting in an average overall survival of less than 8 months from diagnosis. Little is known about the cooperativity and an in-depth understanding of the biological and functional consequences of STK11 and KEAP1 co-mutation is an urgent clinical need that is essential to identify effective therapeutic targets.

Methods

We sequentially profiled 1,235 patients with metastatic LUAD by next generation sequencing (MSK-IMPACT). We used CRISPR/Cas9 to create stable knockouts of STK11, KEAP1, or both genes, in three LUAD lines. We performed cell proliferation, bulk RNAsequencing. Furthermore, we performed CRISPR/Cas9 screens in isogenic in vitro models using a curated “druggable genome” sgRNA library that targets 1,463 genes.

Results

STK11/KEAP1 co-mutation predicts short overall survival in patients with LUAD. STK11/KEAP1 co-mutation promotes tumor cell proliferation and migration in vitro and significantly enhanced tumor growth in vivo. Bulk RNA sequencing demonstrated that STK11/KEAP1 co-mutant cells have higher expression of genes involved in ferroptosis protection and are resistant to ferroptosis inducing agents. CRISPR/Cas9 screen identified ferroptosis regulator SCD as an essential gene required for proliferation and survival of STK11/KEAP1 co-mutant cells. Genetic and pharmacological inhibition of SCD1 prevented the growth of STK11/KEAP1 co-mutant cells and sensitized these cells to ferroptosis induction. Finally, in vivo inhibition of SCD1 significantly delayed tumor growth in STK11/KEAP1 co-mutant LUAD.

Conclusions

This study describes, for the first time, ferroptosis evasion as a survival mechanism for STK11/KEAP1 mutant tumors. We identify SCD as an essential gene in STK11/KEAP1 co-mutant LUAD. SCD1 inhibition, either alone or in conjunction with agents targeting ferroptosis, represents a promising strategy to improve outcomes in this cohort of patients with limited therapeutic options and poor prognosis.

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

Background

CFI-402257 (CFI) is a selective oral inhibitor of TTK protein kinase, a critical regulator of the mitotic spindle assembly checkpoint, is overexpressed in BC and enhances activity of Px in BC xenografts.

Methods

Define recommended phase II dose (RP2D) of CFI in combination with weekly Px using 3+3 escalation. Patients with HER2- advanced BC with adequate organ function, PS=0-1, previously treated with 1 or more non-taxane chemotherapy, were eligible. CFI was given on a 2-day on, 5-day off schedule with Px 80mg/m² on day 1, 8, 15 every 28 days. Starting dose, based on the CFI phase I study, was 84mg PO. Five dose levels (DL) were planned: 84, 112, 168, 210 and 252mg.

Results

29 patients received a total of 169 cycles. Median age was 58 years; 90% ER+/HER2-; 45% PS=1; 21% 3 or more prior chemotherapy regimens (76% received CDK4/6 inhibitors). Grade (G) 3 or more ANC was reported in 66%, G4 in 39%, and 2 patients had infection (febrile neutropenia and skin). Five patients met criteria for dose limiting toxicity (DL3=2; DL4=2; DL5=1): all were G4 ANC. ANC appeared dose dependent and G4 ANC was only reported in DL3, 4 and 5. Increased age was also associated with higher likelihood of G4 ANC (median age of patients with G4 ANC 68 years vs. 51 years; p=0.0025). Adverse events related to CFI and or Px G2 or more included: alopecia (3%), fatigue (10%) and nausea (3%). Partial response was reported for 3 patients.

Conclusions

CFI plus Px has a manageable toxicity profile, with anticancer activity in this heavily pretreated population. Expansion at DL3 (168mg) is ongoing; updated safety/efficacy data will be presented at the meeting.

Clinical trial identification

CCTG IND.236; NCT03568422.

Legal entity responsible for the study

Queen's University.

Funding

CCTG is supported by the Canadian Cancer Society (704970). This study was supported by a SU2C Canada - Canadian Cancer Society Breast Cancer Dream Team Research Funding (SU2C-AACR-DT-18-15) and OICR, funding provided by the Government of Ontario.

Disclosure

M. Mates: Honoraria (self), Advisory/Consultancy: Seagen; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: GenomicHealth; Honoraria (self), Advisory/Consultancy: BMS. P. Bedard: Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): Servier; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): SignalChem; Research grant/Funding (institution): PTC Therapeutics; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): Mersana; Research grant/Funding (institution): Immunomedics. J. Hilton: Advisory/Consultancy, DSBM: BMS; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Merck; Research grant/Funding (institution): GSK. K.A. Gelmon: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy, Research grant/Funding (self): Novartis; Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy: Oncotheryon; Advisory/Consultancy: NanoString; Advisory/Consultancy: Merck; Advisory/Consultancy: Mylan; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Genomic Health; Advisory/Consultancy, Research grant/Funding (self): BMS; Research grant/Funding (self): Expert Testimony; Research grant/Funding (self): Genentech. A. Awan: Advisory/Consultancy: Eli Lily; Advisory/Consultancy: Exact Sciences; Advisory/Consultancy: Exactis; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Honoraria (self): Apotex; Honoraria (self), Travel/Accommodation/Expenses: Roche. X. Song: Advisory/Consultancy, attended advisory board meetings: Novartis; Advisory/Consultancy, attended advisory board meetings: Merck; Advisory/Consultancy, attended advisory board meetings: Pfizer. C. Lohrisch: Advisory/Consultancy: AstraZeneca. M. Bray: Full/Part-time employment, CSO: Treadwell Therapeutics. All other authors have declared no conflicts of interest.