Array BioPharma Announces BRAFTOVI + MEKTOVI + Cetuximab Meet Primary Endpoints of ORR and OS in Phase 3 BEACON CRC Trial Interim Analysis for the Treatment of BRAF(V600E)-mutant Metastatic Colorectal Cancer

- BRAFTOVI combinations showed statistically significant improvement in ORR and OS versus control -

- BRAFTOVI + MEKTOVI + cetuximab reduced the risk of death by 48% versus control -

- Potential to be the first chemotherapy-free, targeted regimen for metastatic CRC patients -

- Array intends to submit these data for marketing approval in 2H19 -

BOULDER, CA, USA I May 21, 2019 I Array BioPharma Inc. (Nasdaq: ARRY) today announced positive results from the interim analysis of the Phase 3 BEACON CRC trial evaluating the combination of BRAFTOVI® (encorafenib), a BRAF inhibitor, MEKTOVI® (binimetinib), a MEK inhibitor, and ERBITUX® (cetuximab), an anti-EGFR antibody (BRAFTOVI Triplet), in patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC), following one or two prior lines of therapy. The trial met both primary endpoints of confirmed objective response rate (ORR), as assessed by Blinded Independent Central Review (BICR), and overall survival (OS). Array intends to submit these results of the BEACON CRC trial for marketing approval in the second half of 2019.

Results from the trial showed that BRAF-mutant mCRC patients treated with the BRAFTOVI Triplet demonstrated a statistically significant improvement in ORR (26.1% vs. 1.9%, p<0.0001, per BICR) and OS (median 9.0 months vs. 5.4 months, [HR 0.52, 95% CI (0.39-0.70), p<0.0001]) compared to cetuximab plus irinotecan-containing regimens (Control).

"The BEACON CRC trial is the first Phase 3 trial in patients with BRAFV600E-mutant mCRC and these results show a significant improvement compared to available standard of care options for this patient population," said Scott Kopetz, M.D., Ph.D., FACP, Associate Professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "Given that there are no therapies currently FDA-approved for this patient population, I believe the results of the BEACON CRC trial will be practice-changing."

The analysis of ORR was based on the first 331 randomized patients, while the interim analysis of OS included all 665 randomized patients, and was based on a data cutoff date in February of 2019, approximately two weeks after the last patient was enrolled. Future analyses will assess ORR on the total population and OS with longer follow up.

Results from the secondary endpoint analysis showed that patients treated with the combination of BRAFTOVI and cetuximab (BRAFTOVI Doublet) demonstrated a statistically significant improvement in ORR (20.4% vs. 1.9%, p<0.0001, per BICR) and OS (median 8.4 months vs. 5.4 months, [HR 0.60, 95% CI (0.45-0.79), p=0.0003]) compared to Control.

A descriptive comparison of the BRAFTOVI Triplet to the BRAFTOVI Doublet demonstrated a positive trend across endpoints including ORR and OS [HR 0.79, 95% CI (0.59-1.06), nominal p=0.1164].

In patients receiving one prior line of therapy, ORR as assessed by BICR was 34.3% with the BRAFTOVI Triplet and 22.4% with the BRAFTOVI Doublet, while at this time the OS for both arms is consistent with that seen in the overall population.

"We are pleased to announce positive results from the BEACON CRC trial, including that the BRAFTOVI Triplet reduced the risk of death by 48% versus control," said Ron Squarer, CEO, Array BioPharma. "We are deeply grateful to the patients and investigators whose participation has helped bring us one step closer to delivering a new standard of care for patients with BRAF-mutant mCRC. This has the potential to be the first chemotherapy-free, targeted regimen for mCRC patients, a population with a very high unmet need for effective treatments."

As demonstrated in the control arm of the BEACON CRC trial and consistent with historical data, patients with BRAF-mutant mCRC generally have a poor prognosis with currently available treatments and currently there are no FDA-approved therapies specifically indicated for this high unmet need population. [1-12,14] BRAF mutations are estimated to occur in up to 15% of patients with mCRC and V600E is the most common mutation. [1-3,12-14]

The BRAFTOVI Triplet and Doublet were generally well-tolerated with no unexpected toxicities. The safety profiles of the BRAFTOVI Triplet and Doublet were consistent with prior reported experience with each regimen and with effects of MEK, RAF and EGFR therapies.

In March 2019, the National Comprehensive Cancer Network® (NCCN®) updated their Clinical Practice Guidelines in Oncology for Colon and Rectal Cancer to include BRAFTOVI in combination with MEKTOVI and an anti-EGFR antibody as a Category 2A treatment for patients with BRAFV600E-mutant mCRC, after failure of one or two prior lines of therapy for metastatic disease. The NCCN based their recommendation on data from the safety lead-in of the BEACON CRC trial.

On August 7, 2018, Array announced that the FDA granted Breakthrough Therapy Designation to BRAFTOVI, in combination with MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease.

The triplet combination of BRAFTOVI, MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC is investigational and not approved by the FDA.

About Colorectal Cancer
Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.4 million new diagnoses in 2012. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer. [15] In the U.S. alone, an estimated 140,250 patients were diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease each year. [16] BRAF mutations are estimated to occur in up to 15% of patients with mCRC and represent a poor prognosis for these patients. [1-3,12,14] The V600 mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF. [12-13] Several irinotecan and cetuximab-containing regimens, similar to the BEACON CRC control arm, have established observed historical published benchmarks in BRAFV600E-mutant mCRC patients, whose disease has progressed after one or two prior lines of therapy. These benchmarks include ORR of 4% to 8%, mPFS of 2 to 3 months and median OS of 4 to 6 months. [1-8] BRAFV600E-mutant mCRC is an area of high unmet need as there are currently no FDA-approved therapies specifically indicated for patients with BRAF-mutant mCRC, and these patients derive limited benefit from available chemotherapy regimens. [9-11] For more information about BRAFV600E-mutant mCRC visit www.brafmcrc.com.

About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of BRAFTOVI, MEKTOVI and ERBITUX in patients with BRAFV600E-mutant mCRC whose disease has progressed after one or two prior regimens. BEACON CRC is the first and only Phase 3 trial designed to test a BRAF/MEK combo targeted therapy in BRAFV600E-mutant mCRC. Thirty patients were treated in the safety lead-in and received the triplet combination (BRAFTOVI 300 mg daily, MEKTOVI 45 mg twice daily and ERBITUX per label). Of the 30 patients, 29 had a BRAFV600 mutation. Microsatellite instability high, resulting from defective DNA mismatch repair, was detected in only 1 patient. As previously announced, the triplet combination demonstrated good tolerability, supporting initiation of the randomized portion of the trial. The randomized portion of the BEACON CRC trial is designed to assess the efficacy of BRAFTOVI in combination with ERBITUX with or without MEKTOVI compared to ERBITUX and irinotecan-based therapy. 665 patients were randomized 1:1:1 to receive the triplet combination, the doublet combination (BRAFTOVI and ERBITUX) or the control arm (irinotecan-based therapy and ERBITUX). The study has been amended to include an interim analysis of endpoints including ORR. The primary overall survival endpoint is a comparison of the triplet combination to the control arm. Secondary endpoints address efficacy of the doublet combination compared to the control arm, and the triplet combination compared to the doublet therapy. Other secondary endpoints include PFS, duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial is being conducted at over 200 investigational sites in North America, South America, Europe and the Asia Pacific region. The BEACON CRC trial is being conducted with support from Ono Pharmaceutical Co. Ltd., Pierre Fabre and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

The triplet combination of BRAFTOVI, MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC is investigational and not approved by the FDA.

About BRAFTOVI + MEKTOVI
BRAFTOVI is an oral small molecule BRAF kinase inhibitor and MEKTOVI is an oral small molecule MEK inhibitor which target key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma, colorectal cancer, non-small cell lung cancer and others. In the U.S., BRAFTOVI + MEKTOVI are approved for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma. In Europe, the combination is approved for adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation, as detected by a validated test. In Japan, the combination is approved for unresectable melanoma with a BRAF mutation.

Array has exclusive rights to BRAFTOVI and MEKTOVI in the U.S. and Canada. Array has granted Ono Pharmaceutical Co. Ltd., exclusive rights to commercialize both products in Japan and South Korea, Medison exclusive rights to commercialize both products in Israel and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Latin American and Asia (excluding Japan and South Korea).

BRAFTOVI + MEKTOVI have received regulatory approval in the United States, European Union, Australia and Japan. The Swiss Medicines Agency (Swissmedic) is currently reviewing the Marketing Authorization Applications for BRAFTOVI and MEKTOVI submitted by Pierre Fabre.

Indications and Usage
BRAFTOVI® (encorafenib) and MEKTOVI® (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.

About Array BioPharma
Array BioPharma Inc. is a fully integrated biopharmaceutical company focused on the discovery, development and commercialization of transformative and well-tolerated targeted small molecule drugs to treat patients afflicted with cancer and other high-burden diseases. Array markets BRAFTOVI® (encorafenib) capsules in combination with MEKTOVI® (binimetinib) tablets for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation in the United States and with partners in other major worldwide markets. Array's lead clinical programs, encorafenib and binimetinib, are being investigated in over 30 clinical trials across a number of solid tumor indications, including a Phase 3 trial in BRAF-mutant metastatic colorectal cancer. Array's pipeline includes several additional programs being advanced by Array or current license-holders, including the following programs currently in registration trials: selumetinib (partnered with AstraZeneca), LOXO-292 (partnered with Eli Lilly), ipatasertib (partnered with Genentech), tucatinib (partnered with Seattle Genetics) and ARRY-797. Vitrakvi® (larotrectinib, partnered with Bayer AG) is approved in the United States and Ganovo® (danoprevir, partnered with Roche) is approved in China. For more information on Array, please visit www.arraybiopharma.com or follow @arraybiopharma on Twitter and LinkedIn.

References 
[1] Saridaki, et al., PLoS One. 2013. 
[2] Loupakis, et al., Br J Cancer. 2009.
[3] Corcoran, et al., Cancer Discovery. 2012
[4] Kopetz, et al., ASCO 2017.
[5] De Roock, et al., Lancet Oncol. 2010. 
[6] Ulivi, et al., J Transl Med. 2012. 
[7] Peeters, et al., ASCO 2014.
[8] Seymour, et al., Lancet Oncol. 2013 (supplementary appendix).
[9] NCCN Clinical Practice Guidelines in Oncology for Colon Cancer. Version 3.2018. National Comprehensive Cancer Network. 
[10] Van Cutsem, et al., Annals of Oncology. 2016. 
[11] Ursem, et al., Gastrointest Cancer, 2018. 
[12] Sorbye, et al., PLoS One. 2015.
[13] Safaee, et al. PLoS One. 2012.
[14] Vecchione, et al., Cell. 2016.
[15] Global Cancer Facts & Figures 3rd Edition. American Cancer Society. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/global-cancer-facts-and-figures/global-cancer-facts-and-figures-3rd-edition.pdf. Accessed January 2018.
[16] Cancer Facts & Figures 2018. American Cancer Society. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed January 2018.
[17] BRAFTOVI® (encorafenib) Prescribing Information. Array BioPharma Inc., June 2018
[18] MEKTOVI® (binimetinib) Prescribing Information. Array BioPharma Inc., June 2018

® National Comprehensive Cancer Network, Inc. 2019. To view the most recent and complete version of the guideline, go online to NCCN.org.

SOURCE: Array Biopharma

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