• In the phase Ib GO42144 study, divarasib in combination with cetuximab, an anti-EGFR therapy, led to a confirmed overall response in 62% of people with advanced colorectal cancer
• The treatment combination demonstrated a manageable safety profile
• The data presented at AACR 2023 further support Roche's programme to develop divarasib as single-agent or in combination for treating solid tumours

Basel, 18 April 2023 - Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today new positive data from the phase Ib GO42144 study, which show that treatment with the KRAS G12C inhibitor, divarasib (GDC-6036), in combination with anti-EGFR therapy, cetuximab, led to a confirmed overall response in 62% of people with advanced or metastatic KRAS G12C-positive colorectal cancer (CRC). Divarasib in combination with cetuximab demonstrated a manageable safety profile. The data were presented at the American Association for Cancer Research (AACR) Annual Meeting, 17 April 2023 at 14:50 ET.¹

CRC is the third most common cancer worldwide and the global burden is growing, with the incidence rate predicted to increase by 56% between 2020 and 2040 to more than three million new cases per year.² It is also one of the leading causes of cancer-related deaths, with KRAS mutations in CRC associated with poorer prognosis and increased tumour aggressiveness.³

“These data reinforce the potentially best-in-class-profile of divarasib together with EGFR inhibition in people who have KRAS G12C mutated CRC and support further investigation of this combination,” said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. “KRAS mutations are associated with a poor prognosis across multiple tumour types, including colorectal cancer, and these data bring us one step closer to delivering much needed new treatment options for patients with KRAS G12C mutations.”

Data from the phase Ib GO42144 study show that treatment with divarasib in combination with cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, demonstrate promising clinical activity and a manageable safety profile in patients with advanced or metastatic KRAS G12C-positive CRC. An unconfirmed overall response was achieved in 66% (n=19/29) of patients and confirmed overall response in 62% (n=18/29) of patients. All patients experienced at least one treatment-related adverse event (TRAE), with grade ≥3 TRAEs occurring in 41% (n=12/29) of patients. No patients discontinued the trial due to AEs.¹

Research demonstrates that blocking EGFR may sensitise the tumour to KRAS G12C inhibition in CRC and may overcome resistance to KRAS G12C inhibition alone. These data reinforce previous observations regarding divarasib treatment in different settings and underline its strong anti-tumour activity in KRAS G12C mutated tumours.⁴ This includes data presented at the Annual Meeting of the European Society of Medical Oncology (ESMO) 2022, which demonstrated that divarasib as a single-agent achieved an unconfirmed overall response in 41% (16/39) and a confirmed overall response in 31% (12/39) of patients with KRAS G12C-positive CRC treated with the 400 mg dose.⁵

Roche’s ongoing development programme for divarasib aims to further improve upon treatment outcomes in solid tumours with the KRAS G12C mutation. Divarasib is being investigated in phase I trials as single-agent and in combination with other anticancer therapies for the treatment of non-small cell lung cancer (NSCLC), CRC, and other solid tumours. Divarasib is also being investigated in a phase II/III global study [B-FAST; NCT03178552] in people with advanced NSCLC.⁶

About GO42144
The ongoing phase I/Ib dose-escalation and dose-expansion GO42144 study [NCT04449874] is evaluating the safety, pharmacokinetics (PK) and preliminary activity of divarasib (GDC-6036) as single-agent and in combination with other anti-cancer therapies in patients with advanced or metastatic solid tumours with a KRAS G12C mutation.⁷ The tumours being investigated include non-small cell lung cancer, colorectal cancer (CRC) and advanced solid tumours.

In phase Ib of the study, 29 patients with advanced or metastatic KRAS G12C-positive CRC, who had received two median lines of prior metastatic therapy, were administered divarasib with cetuximab until intolerable toxicity or disease progression. The median time on study treatment was 5.5 months. Endpoints included safety (NCI0-CTCAE v5), PK and preliminary anti-tumour activity (RECIST V1.1).

About divarasib
Divarasib (GDC-6036) is an investigational, oral, highly potent and selective KRAS G12C inhibitor.⁸ It works by irreversibly locking the KRAS G12C oncoprotein in its inactive state, preventing the tumour cells from growing. It is being investigated in solid tumours, including non-small cell lung cancer and colorectal cancer and other cancer types. Further studies are ongoing to establish its potential in the KRAS G12C inhibitor space.^6,7

About colorectal cancer and the KRAS G12C mutation
Colorectal cancer (CRC) is the third most common cancer type worldwide. In 2020, almost two million cases were diagnosed, and this is estimated to increase to more than three million new cases per year by 2040. It is one of the leading causes of cancer-related deaths and treatment options remain limited for people with advanced CRC.² For people whose disease has progressed after receiving two rounds of treatment, nearly half in Europe and in the US will receive no further treatment at all.^9,10 This may be due to limited options for third-line treatment, coupled with poor overall survival from second to third-line treatment.^11,12

KRAS mutations are found in approximately 40% of CRC cases, and the KRAS G12C mutation in approximately 4% of CRC cases. KRAS mutations are linked to poorer prognosis and more aggressive tumour growth, highlighting the need for new treatment options for advanced CRC.³

About Roche
Founded in 1896 in Basel, Switzerland, as one of the first industrial manufacturers of branded medicines, Roche has grown into the world’s largest biotechnology company and the global leader in in-vitro diagnostics. The company pursues scientific excellence to discover and develop medicines and diagnostics for improving and saving the lives of people around the world. We are a pioneer in personalised healthcare and want to further transform how healthcare is delivered to have an even greater impact. To provide the best care for each person we partner with many stakeholders and combine our strengths in Diagnostics and Pharma with data insights from the clinical practice.

In recognising our endeavor to pursue a long-term perspective in all we do, Roche has been named one of the most sustainable companies in the pharmaceuticals industry by the Dow Jones Sustainability Indices for the thirteenth consecutive year. This distinction also reflects our efforts to improve access to healthcare together with local partners in every country we work.

Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan.

For more information, please visit www.roche.com.

All trademarks used or mentioned in this release are protected by law.

References
[1] Desai J, et al. Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation. Presented at American Association for Cancer Research Annual Meeting 2023, 15-19 April 2023; Florida, United States.
[2] International Agency for Research on Cancer. Colorectal Cancer Awareness Month. [Internet; cited April 2023]. Available from: https://www.iarc.who.int/featured-news/colorectal-cancer-awareness-month-2022/.
[3] Zhu G, et al. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Molecular Cancer. 2021;20:143.
[4] Amodio V, et al. EGFR Blockade Reverts Resistance to KRAS G12C Inhibition in Colorectal Cancer. Cancer Discovery. 2020;10(8):1129-1139.
[5] Desai J, et al. Phase IA study to evaluate GDC-6036 monotherapy in patients with colorectal cancer (CRC) with KRAS G12C mutation. Presented at European Society for Medical Oncology 2022, 9-13 September, 2022; Paris, France.
[6] Roche data on file.
[7] Clinical Trials.gov. A study to evaluate the safety, pharmacokinetics, and activity of GDC-6036 alone or in combination in participants with advanced or metastatic solid tumors with a KRAS G12C mutation. [Internet; cited April 2023]. Available from: https://clinicaltrials.gov/ct2/show/NCT04449874.
[8] Purkey H, et al. Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers. American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND11.
[9] Tampellini M, et al. Treatment of patients with metastatic colorectal cancer in a real-world scenario: probability of receiving second and further lines of therapy and description of clinical benefit. Clin Colorectal Cancer. 2017;16(4):372-376.
[10] Abrams TA, et al. Chemotherapy usage patterns in a US-wide cohort of patients with metastatic colorectal cancer. J Natl Cancer Inst. 2014;106(2):djt371.
[11] Carter NJ, et al. Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer. Drugs Aging. 2014;31(1):67-78.
[12] Hanna N, et al. Survival benefit associated with the number of chemotherapy/biologic treatment lines in 5,129 metastatic colon cancer patients. Poster presented at: The American Society of Clinical Oncology 2014 Gastrointestinal Cancers Symposium; 2014 Jan 18; San Francisco, CA, USA. Abstract #559.

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