Author: Klempner, Samuel J. ; Peguero, Julio A. ; Kopetz, Scott E. ; Yan, Xiaohong ; Cruz-Correa, Marcia ; Barve, Minal ; Velastegui, Karen ; Paulson, Andrew Scott ; Uboha, Nataliya V. ; Der-Torossian, Hirak ; Anderes, Kenna ; Pelster, Meredith S. ; Sabari, Joshua K. ; Jänne, Pasi A. ; Bekaii-Saab, Tanios S. ; Saltzman, Joel ; Yaeger, Rona

Abstract:

Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2–7.6). Median progression-free survival was 6.9 months (95% CI, 5.7–7.4) and median overall survival was 15.9 months (95% CI, 11.8–18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3–4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance.

Significance::

Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer.This article is featured in Selected Articles from This Issue, p. 897See co-corresponding author Rona Yaeger discuss this research article, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932606282/f27a6e46f4

01 May 2024·Cancer discovery

Sotorasib Is a Pan-RASG12C Inhibitor Capable of Driving Clinical Response in NRASG12C Cancers

Article

Author: Barnes, Haley ; Ehnstrom, Sara ; Corcoran, Ryan B. ; Brais, Lauren K. ; Tanaka, Noritaka ; Kapner, Kevin S. ; Fece de la Cruz, Ferran ; Norden, Bryanna L. ; Aguirre, Andrew J. ; Rubinson, Douglas A. ; Lemke, Christopher T. ; Rosenthal, Michael H. ; Morales-Giron, Alvin A.

Abstract:

KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical efficacy in KRASG12C tumors. Because amino acid sequences of the three main RAS isoforms—KRAS, NRAS, and HRAS—are highly similar, we hypothesized that some KRASG12C inhibitors might also target NRASG12C and/or HRASG12C, which are less common but critical oncogenic driver mutations in some tumors. Although some inhibitors, like adagrasib, were highly selective for KRASG12C, others also potently inhibited NRASG12C and/or HRASG12C. Notably, sotorasib was five-fold more potent against NRASG12C compared with KRASG12C or HRASG12C. Structural and reciprocal mutagenesis studies suggested that differences in isoform-specific binding are mediated by a single amino acid: Histidine-95 in KRAS (Leucine-95 in NRAS). A patient with NRASG12C colorectal cancer treated with sotorasib and the anti-EGFR antibody panitumumab achieved a marked tumor response, demonstrating that sotorasib can be clinically effective in NRASG12C-mutated tumors.

Significance::

These studies demonstrate that certain KRASG12C inhibitors effectively target all RASG12C mutations and that sotorasib specifically is a potent NRASG12C inhibitor capable of driving clinical responses. These findings have important implications for the treatment of patients with NRASG12C or HRASG12C cancers and could guide design of NRAS or HRAS inhibitors.See related commentary by Seale and Misale, p. 698.This article is featured in Selected Articles from This Issue, p. 695

01 Mar 2024·Molecular oncology

FBXL16 promotes cell growth and drug resistance in lung adenocarcinomas with KRAS mutation by stabilizing IRS1 and upregulating IRS1/AKT signaling

Article

Author: Long, Weiwen ; Morel, Marion

Lung cancer is the leading cause of cancer‐related deaths worldwide. Lung adenocarcinomas (LUADs) are a major subtype of non‐small‐cell lung cancers (NSCLCs). About 25% of LUADs harbor GTPase KRAS mutations associated with poor prognosis and limited treatment options. While encouraging tumor response to novel covalent inhibitors specifically targeting KRASG12C has been shown in the clinic, either intrinsic resistance exists or acquired therapeutic resistance arises upon treatment. There is an unmet need to identify new therapeutic targets for treating LUADs with activating KRAS mutations, particularly those with resistance to KRASG12C inhibitor(s). In this study, we have revealed that F‐box/LRR‐repeat protein 16 (FBXL16) is selectively upregulated in LUAD with KRAS mutations. It promotes LUAD cell growth and transforms lung epithelial cells. Importantly, FBXL16 depletion greatly enhances sensitivity to the KRASG12C inhibitor (sotorasib) in resistant cells by downregulating phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (PKB; also known as AKT) signaling. Mechanistically, FBXL16 upregulates insulin receptor substrate 1 (IRS1) protein stability, leading to an increase of IGF1/AKT signaling, thereby promoting cell growth and migration. Taken together, our study highlights the potential of FBXL16 as a therapeutic target for treating LUAD with KRAS activating mutations.

News (Medical) associated with Mutant GTPase KRASG12C Inhibitors(AstraZeneca)

22 Jun 2024

·pipelinereview.com

Bristol Myers Squibb Announces U.S. FDA Accelerated Approval of KRAZATI® (adagrasib) in Combination with Cetuximab for Adult Patients with Previously Treated KRAS G12C-Mutated Locally Advanced or Metastatic Colorectal Cancer (CRC)

Approval based on results from the Phase 1/2 KRYSTAL-1 study where KRAZATI in combination with cetuximab showed an objective response rate of 34% in pretreated patients with locally advanced or metastatic CRC harboring a KRAS G12C mutation 1 Second FDA approval for KRAZATI – reinforcing its potential across tumor types PRINCETON, NJ, USA I June 21, 2024 I Bristol Myers Squibb (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval for KRAZATI ® (adagrasib) in combination with cetuximab as a targeted treatment option for adult patients with KRAS G12C -mutated locally advanced or metastatic colorectal cancer (CRC), as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR) results. Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial. “CRC with a KRAS G12C mutation occurs in approximately 3-4% of CRC patients and has historically been challenging to treat,” 2 said Rona Yaeger, MD, Gastrointestinal Oncologist & Early Drug Development Specialist, Memorial Sloan Kettering Cancer Center. “The FDA approval of KRAZATI combined with cetuximab now provides a new treatment option to these patients when their tumors do not respond well to prior therapies.” The approval is based on results from cohorts of the Phase 1/2 KRYSTAL-1 open-label study which evaluated KRAZATI (600 mg tablets administered orally twice daily) in combination with cetuximab in 94 patients with heavily pretreated CRC harboring a KRAS G12C mutation. The study met its primary endpoint, with a confirmed ORR of 34% (n=94, 95% CI: 25-45) for KRAZATI with cetuximab, all of which were partial responses. The median DOR, one of the secondary endpoints, was 5.8 months (95% CI: 4.2-7.6). 1 Current late-line standard of care options result in limited response rates (ORR 1-6%) after progression on chemotherapy ± VEGF/VEGFR inhibitors. 3,4 KRAZATI is associated with the following Warnings & Precautions: Gastrointestinal adverse reactions including diarrhea, nausea, and vomiting, QTc interval prolongation, hepatotoxicity, and interstitial lung disease (ILD)/pneumonitis. 1 Please see Important Safety Information below. “Today’s approval of KRAZATI in CRC is the second in the U.S. for this therapy and the first for BMS’ recently expanded oncology portfolio. This is an important milestone for BMS and the patients we serve as we deliver on our commitment to provide innovative medicines for cancer,” said Wendy Short Bartie, senior vice president, U.S. Oncology and Hematology at Bristol Myers Squibb. “We are proud to make KRAZATI – the first KRAS G12C inhibitor to be FDA approved beyond non-small cell lung cancer – available to CRC patients, and look forward to further evaluating KRAZATI through our ongoing development program.” In 2022, the FDA granted breakthrough therapy designation for KRAZATI in combination with cetuximab for patients with KRAS G12C -mutated advanced CRC whose cancer has progressed following prior treatment with certain chemotherapy and an anti-VEGF therapy. KRAZATI is an irreversible inhibitor of KRAS G12C with a long half-life (23 hours), dose-dependent pharmacokinetics (PK), and central nervous system (CNS) penetration, which, in combination with cetuximab may enhance inhibition of KRAS-dependent signaling or overcome adaptive feedback. The company partnered with QIAGEN to develop a tissue-based companion diagnostic (CDx) for KRAZATI that is now available. KRAZATI is a registered trademark of Mirati Therapeutics, Inc., a Bristol Myers Squibb company. About KRYSTAL-1 KRYSTAL-1 is an open-label, multicenter, multiple expansion cohort Phase 1/2 trial to determine the safety and efficacy of KRAZATI in patients with advanced colorectal cancer (CRC) that harbor a KRAS G12C mutation. The primary endpoint for the Phase 2 cohort of the KRYSTAL-1 study was objective response rate (ORR). Secondary endpoints included duration of response (DOR). The KRYSTAL-1 study was funded by Mirati Therapeutics, Inc., a Bristol Myers Squibb company. Select Safety Profile from KRYSTAL-1 The safety profile for KRAZATI plus cetuximab was evaluated in patients with KRAS G12C -mutated, locally advanced or metastatic CRC, and is consistent with previous reports and known safety profile of each drug individually. Serious adverse reactions occurred in 30% of 94 patients who received KRAZATI in combination with cetuximab. The most common adverse reactions (≥20%) were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, dizziness, cough, constipation, and peripheral neuropathy. 1 About Colorectal Cancer Colorectal cancer (CRC) is cancer that develops in the colon or the rectum, which are part of the body’s digestive, or gastrointestinal, system. 5 CRC is the third most commonly diagnosed cancer in the world. 6 In 2024, it is estimated that there will be approximately 106,590 new cases of the disease in the U.S.; it is the second leading cause of cancer-related deaths in the U.S. among men and women combined. 7 KRAS is the most frequently mutated oncogene in human cancer and is one that drives oncogenesis in up to 50% of patients with CRC. 2 The KRAS G12C mutation occurs in approximately 3-4% of CRC cases. 2 About KRAZATI ® (adagrasib) KRAZATI (adagrasib) is a highly selective and potent oral small-molecule inhibitor of KRAS G12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRAS G12 C -mutated cancers, as the KRAS G12C protein regenerates every 24-48 hours. 8 KRAS G12C mutations act as oncogenic drivers and occur in approximately 14% of non-small cell lung cancer (NSCLC; adenocarcinoma) and 3% of several other cancers. 9,10 In 2022, KRAZATI was granted accelerated approval for treatment of adult patients with KRAS G12C -mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial. KRAZATI continues to be evaluated as a monotherapy and in combination with other anti-cancer therapies in patients with advanced KRAS G12C -mutated solid tumors, including NSCLC and CRC. Please see U.S. Full Prescribing Information for KRAZATI . INDICATIONS KRAZATI in combination with cetuximab is indicated for the treatment of adult patients with KRAS G12C -mutated locally advanced or metastatic colorectal cancer (CRC), as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. KRAZATI , as a single agent, is indicated for the treatment of adult patients with KRAS G12C -mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy. These indications are approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for these indications may be contingent upon verification and description of a clinical benefit in confirmatory trials. Please see U.S. Full Prescribing Information for KRAZATI . Bristol Myers Squibb: Creating a Better Future for People with Cancer Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research platforms uniquely position the company to approach cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop, and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, please visit BMS.com or follow us on LinkedIn , X (formerly Twitter), YouTube , Facebook , and Instagram . 1 KRAZATI. Prescribing Information. Princeton, NJ. Mirati Therapeutics, Inc., a Bristol Myers Squibb company; 2024. 2 Yaeger, R., Weiss, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. New England Journal of Medicine . 2023;388(1), 44–54. https://doi.org/10.1056/nejmoa2212419 3 Prager, G., et al. Trifluridine–Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. New England Journal of Medicine . 2023 May 4;388(18). https://www.nejm.org/doi/full/10.1056/NEJMoa2214963 4 Grothey, A., et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet . https://pubmed.ncbi.nlm.nih.gov/23177514/ 5 What is colorectal cancer? American Cancer Society. (n.d.) https://www.cancer.org/cancer/colon-rectal-cancer/about/what-is-colorectal-cancer.html 6 Globocan 2020, World https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf 7 Colorectal cancer statistics: How common is colorectal cancer? American Cancer Society. (n.d.). https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html 8 Hallin J, Engstrom LD, Hargis L, et al. The KRAS Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients. Cancer Discov . 2020;10(1):54-71 9 Campbell et al, Nature Genetics 2016 “Distinct patterns of somatic genome alterations in lung adenocarcinomas 10 Nassar, A., et al. Distribution of KRASG12C Somatic Mutations across Race, Sex, and Cancer Type. New England Journal of Medicine, 384:185-187. https://doi.org/10.1056/nejmc2030638 SOURCE: Bristol Myers Squibb

Drug ApprovalClinical ResultPhase 3Accelerated ApprovalBreakthrough Therapy

26 Oct 2023

·www.globenewswire.com

Kura Oncology Announces First Patient Dosed in FIT-001 Trial of Next-Generation Farnesyl Transferase Inhibitor KO-2806

– Phase 1 dose-escalation study to evaluate KO-2806 as a monotherapy and in combination with targeted therapies in KRASG12C-mutant NSCLC and ccRCC – Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, today announced that the first patient has been dosed in the FIT-001 Phase 1 dose-escalation trial of KO-2806, the Company’s next-generation farnesyl transferase inhibitor (FTI) for the treatment of advanced solid tumors. “We’re excited to advance our next-generation FTI drug candidate into the clinical setting, underscoring our commitment and sense of urgency to develop novel therapies for cancer indications with high unmet medical needs,” said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. “Our understanding of how to use FTIs to target farnesylated proteins has matured significantly beyond our initial strategy to target HRAS mutant tumors. With the success of targeted therapies such as KRASG12C inhibitors, tyrosine kinase inhibitors and EGFR inhibitors, there is now considerable focus on the development of companion therapeutics that have potential to drive enhanced antitumor activity and address mechanisms of innate and adaptive resistance. We will focus the development of KO-2806 initially in combinations in the areas of lung cancer and renal cell carcinomas and, if successful, we believe KO-2806 could become the ideal combination partner for a wide range of targeted therapies.” FIT-001 is a Phase 1, first-in-human, multicenter, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of KO-2806 when administered as monotherapy and in combination with targeted therapies. Concurrent with the monotherapy dose escalation, the Company plans to evaluate KO-2806 in dose-escalation combination cohorts with other targeted therapies, beginning in KRASG12C-mutant non-small cell lung cancer (NSCLC) and clear cell renal cell carcinoma (ccRCC). For more information regarding FIT-001, please visit www.clinicaltrials.gov (identifier: NCT06026410). KO-2806 is a next-generation inhibitor of farnesyl transferase designed to improve upon potency, pharmacokinetic and physicochemical properties of earlier FTI drug candidates. Earlier this month at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Kura presented promising preclinical data supporting the rationale for combining KO-2806 with distinct classes of targeted therapies, including tyrosine kinase inhibitors, KRASG12C inhibitors and KRASG12D inhibitors. Additional information about clinical trials for KO-2806 can be found at https://kuraoncology.com/clinical-trials/#farnesyl-transferase-inhibitor. Kura Oncology is a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer. The Company’s pipeline consists of small molecule drug candidates that target cancer signaling pathways. Ziftomenib is a once-daily, oral drug candidate targeting the menin-KMT2A protein-protein interaction for the treatment of genetically defined acute myeloid leukemia (AML) patients with high unmet need. Kura is currently enrolling patients in a Phase 2 registration-directed trial of ziftomenib in NPM1-mutant relapsed or refractory AML (KOMET-001). The Company is also conducting a series of studies to evaluate ziftomenib in combination with current standards of care, beginning with venetoclax/azacitidine and standard induction cytarabine/daunorubicin chemotherapy in NPM1-mutant and KMT2A-rearranged newly diagnosed and relapsed/refractory AML (KOMET-007). Tipifarnib, a potent and selective FTI, is currently in a Phase 1/2 trial in combination with alpelisib for patients with PIK3CA-dependent head and neck squamous cell carcinoma (KURRENT-HN). Kura is also preparing to evaluate KO-2806, a next-generation FTI, in a Phase 1 dose-escalation trial as a monotherapy and in combination with other targeted therapies, beginning with KRASG12C-mutant NSCLC and ccRCC (FIT-001). For additional information, please visit Kura’s website at www.kuraoncology.com and follow us on Twitter and LinkedIn. The content above comes from the network. if any infringement, please contact us to modify.

AACRClinical Result

18 Apr 2023

·www.biospace.com

Kura Oncology Reports Preclinical Data Highlighting Synergistic Activity of Farnesyl Transferase Inhibitor in Combination with Targeted Therapies

– Preclinical data support the potential for FTIs in combination with KRASG12C inhibitors and TKIs to prevent or delay emergence of adaptive resistance – – Company preparing to initiate Phase 1 dose-escalation trial (FIT-001) of KO-2806, a next-generation FTI – SAN DIEGO, April 17, 2023 (GLOBE NEWSWIRE) -- Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, today reported preclinical data supporting the potential use of farnesyl transferase inhibitors (FTIs) to treat various types of solid tumors in combination with targeted therapies, including KRASG12C inhibitors and anti-angiogenic tyrosine kinase inhibitors (TKIs). These data were featured in two poster presentations at the American Association for Cancer Research (AACR) Annual Meeting on Sunday, April 16 in Orlando. Copies of the posters are available on Kura’s website at . New preclinical data in the poster titled, ‘Tipifarnib synergizes with a TKI in clear cell renal cell carcinoma models,’ demonstrates the synergistic activity of tipifarnib and axitinib, a TKI approved to treat advanced renal cell carcinoma (RCC), in cell- and patient-derived RCC xenograft models. These data support the potential to administer an FTI in combination with a TKI for the treatment of RCC, and studies are ongoing to further evaluate the mechanistic basis of the synergy observed with the combination. In addition, new findings were presented in the poster titled, ‘Combination of tipifarnib with KRASG12C inhibitors to prevent adaptive resistance,’ evaluating the effects of tipifarnib in combination with adagrasib and sotorasib in cell line and xenograft models of KRASG12C mutant non-small cell lung cancer (NSCLC). These data reveal that the addition of tipifarnib leads to significant tumor regression in xenograft models and suppresses mTOR signaling reactivation relative to treatment with the KRASG12C inhibitors alone. These results support further preclinical studies to determine the mechanism of action for the combination. “Although targeted therapies have demonstrated meaningful clinical activity, including objective responses, across a range of solid tumors, over time adaptive resistance almost invariably emerges, limiting the ability of the targeted therapies to drive sustained clinical benefit. Yesterday, we presented encouraging preclinical data that highlight the potential for FTIs to prevent or delay emergence of resistance to certain classes of targeted therapies,” said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. “We believe these promising preclinical data strongly support our rationale to combine KO-2806 with KRASG12C mutant inhibitors and TKIs in NSCLC and RCC, respectively.” In parallel to the clinical evaluation of tipifarnib, the Company is advancing KO-2806, a potent inhibitor of farnesyl transferase that was designed to improve upon potency, pharmacokinetic and physicochemical properties of earlier FTI drug candidates. The Company expects to initiate the Phase 1 first-in-human study (FIT-001) later this year to assess safety, tolerability and preliminary antitumor activity of KO-2806 as a monotherapy and in combination with other targeted therapies in adult patients with advanced solid tumors. Following completion of the dose escalation as a monotherapy, Kura plans to evaluate KO-2806 in dose escalation combination cohorts in advanced solid tumors. About Kura Oncology Kura Oncology is a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer. The Company’s pipeline consists of small molecule drug candidates that target cancer signaling pathways. Ziftomenib is a once-daily, oral drug candidate targeting the menin-KMT2A protein-protein interaction for the treatment of genetically defined AML patients with high unmet need. The Company is currently enrolling patients in a Phase 2 registration-directed trial (KOMET-001) of ziftomenib in NPM1-mutant relapsed or refractory AML. Kura is preparing to initiate multiple Phase 1 trials to evaluate ziftomenib in combination with current standards of care in earlier lines of therapy and across multiple patient populations, including NPM1-mutant and KMT2A-rearranged AML. Tipifarnib, a potent and selective FTI, is currently in a Phase 1/2 trial (KURRENT-HN) in combination with alpelisib for patients with PIK3CA-dependent HNSCC. Kura intends to evaluate KO-2806, a next-generation FTI, in a Phase 1 dose-escalation trial (FIT-001) as a monotherapy and in combination with other targeted therapies in adult patients with advanced solid tumors. For additional information, please visit Kura’s website at . Forward-Looking Statements This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, the efficacy, safety and therapeutic potential of tipifarnib and KO-2806, and progress and expected timing of Kura’s drug development programs. Factors that may cause actual results to differ materially include the risk that compounds that appeared promising in early research or clinical trials do not demonstrate safety and/or efficacy in later preclinical studies or clinical trials, the risk that Kura may not obtain approval to market its product candidates, uncertainties associated with performing clinical trials, regulatory filings, applications and other interactions with regulatory bodies, risks associated with reliance on third parties to successfully conduct clinical trials, the risks associated with reliance on outside financing to meet capital requirements, and other risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. You are urged to consider statements that include the words “may,” “will,” “would,” “could,” “should,” “believes,” “estimates,” “projects,” “promise,” “potential,” “expects,” “plans,” “anticipates,” “intends,” “continues,” “designed,” “goal,” or the negative of those words or other comparable words to be uncertain and forward-looking. For a further list and description of the risks and uncertainties the Company faces, please refer to the Company's periodic and other filings with the Securities and Exchange Commission, which are available at Such forward-looking statements are current only as of the date they are made, and Kura assumes no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Contacts Investors: Pete De Spain Senior Vice President, Investor Relations & Corporate Communications (858) 500-8833 pete@kuraoncology.com Media: Alexandra Weingarten Senior Manager, Corporate Communications (858) 500-8822 alexandra@kuraoncology.com

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