KRAS Makes Strides Toward Becoming “Druggable” in GI Cancers in 2020

KRAS has often been referred to over the years as an “undruggable” target. In 1983, KRAS was the first human oncogene to be discovered, yet there are still no drugs approved to target the tumors it drives.¹

However, significant progress was made this year toward effectively hitting KRAS-driven tumors, leading to a great deal of excitement in the field. A number of new agents in development could potentially treat patients with KRAS-mutant gastrointestinal (GI) and other solid tumors.

Why All the Fuss Over KRAS?

Overall, KRAS is the most frequently mutated of the 3 RAS isoforms, making up about 85% of all RAS mutations in cancers.1,2 Mutant KRAS presents most commonly in colorectal cancer (CRC), pancreatic cancer, and lung cancer. KRAS mutations drive 86% of pancreatic ductal adenocarcinomas (PDACs), as well as 41% of CRCs and 32% of lung adenocarcinomas. In each of these tumor types, the KRAS mutations are in codon 12 for a vast majority of cases.

Historical approaches to targeting KRAS-driven tumors have been unsuccessful, with agents showing both a lack of efficacy and high toxicity. But efforts continue in hopes of finding an effective way to treat these alterations because they tend to be associated with a worse prognosis and resistance to targeted therapies.

“Direct targeting of RAS is challenging and so far, has not been fruitful. However, using other strategies, such as synthetic lethality, is an opportunity to develop agents that can effectively treat patients with KRAS-mutated tumors,” Afsaneh Barzi, MD, PhD, a medical oncologist and associate clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope in Duarte, California, said in an interview with Targeted Therapies in Oncology.

Two strategies, the direct targeting of KRAS and targeting KRAS signaling, have emerged, according to Mariano Barbacid, PhD, in a presentation during the 32nd European Organisation for Research and Treatment of Cancer – National Cancer Institute – American Association for Cancer Research Symposium on Molecular Targets and Cancer Therapeutics.³ He explained that direct KRAS targeting is the more effective method because it is more specific to mutant KRAS and, thus, less prone to off-target effects. However, this approach applies only to KRAS G12C mutations. Targeting KRAS signaling is effective against all KRAS mutations but less effective overall and would likely require added therapies to provide greater efficacy. Additionally, this approach could affect normal RAS signaling, which could lead to toxicities.

KRAS G12C Inhibitors

Sotorasib

Activity focused on KRAS G12C took off recently following the discovery of a shallow switch II pocket in the mutant KRAS G12C protein, which enabled the development of covalent inhibitors of KRAS G12C.^1,4

Sotorasib (AMG 510) was one of the first such molecules to enter human clinical trials. The agent traps KRAS G12C in the inactive guanosine diphosphate (GDP)–bound state and inhibits oncogenic signaling and tumorigenesis.⁵

In the phase 1 CodeBreak 100 trial (NCT03600883), sotorasib demonstrated significant disease control in patients with heavily pretreated advanced KRAS G12C–mutant solid tumors. The trial enrolled of total of 129 patients with locally advanced or metastatic solid tumors harboring a KRAS G12C mutation who had received at least 1 prior systemic therapy. The median number of prior systemic therapies for metastatic disease was 3 (range, 0-11).

In the CRC group (n = 42), responses were modest, with an objective response rate (ORR) of 7.1% and a disease control rate (DCR) of 73.8%.

Among other GI cancers included in the study, of 11 patients with pancreatic cancer, 1 had a partial response (PR) and 8 had stable disease (SD). Additionally, 1 patient with appendiceal cancer had a PR at a lower dose than the dose chosen for expansion cohorts.

Updated findings for the GI population at the European Society for Medical Oncology (ESMO) Asia Virtual Congress 2020 showed that the patients with CRC achieved a median progression-free survival (PFS) of 4.0 months (range, 0.7-11.0).⁶ Among those who were treated with the 960-mg dose of sotorasib (n = 25), the median PFS was 4.2 months (range, 1.2-5.7+). This group had an ORR of 12.0% and a DCR of 80.0%.

Comparatively, patients with non–small cell lung cancer (NSCLC; n = 59) demonstrated encouraging responses to treatment with sotorasib, with an ORR of 32.2% and a DCR of 88.1%.⁵

Most patients (96.9%) experienced an adverse event (AE) of any grade during treatment, but just 7.0% led to treatment discontinuation. The most common AEs of any cause included diarrhea (29.5%), fatigue (23.3%), nausea (20.9%), vomiting (17.8%), abdominal pain (17.8%), dyspnea (16.3%), and cough (15.5%). Just 1 event of dyspnea was grade 5.

“The drug is safe, which is an important part of a phase 1 study, and really, there are no major toxicities of the single agent,” Thomas J. Price, MBBS, FRACP, DHlthSc, head of clinical oncology research and the combined Hematology and Medical Oncology Service at The Queen Elizabeth Hospital and clinical professor at The University of Adelaide in South Australia, said to Targeted Therapies in Oncology in an interview. “Their progression-free survival of over 4 months is quite significant when you compare it to some of the other standard therapies in this space, where the PFS would be more around 2 months.…There is a very good signal of activity.”

The phase 2 portion of the CodeBreak 100 trial is ongoing.

Adagrasib

Adagrasib (MRTX849) is another covalent inhibitor of KRAS G12C that irreversibly and selectively binds to KRAS G12C in its inactive GDP-bound state. In the multicohort phase 1/2 KRYSTAL-1 trial (NCT03785249), patients with previously treated KRAS G12C–mutant NSCLC, CRC, and other solid tumors benefited from receiving adagrasib.⁷

During the Symposium on Molecular Targets and Cancer Therapeutics, Melissa L. Johnson, MD, associate director for lung cancer research at Sarah Cannon and a medical oncologist at Tennessee Oncology, both in Nashville, said that “adagrasib is well tolerated and provides durable benefit to patients with colorectal cancer harboring KRAS G12C mutations, as well as KRAS G12C–mutated solid tumors.”

Among patients with CRC specifically (n = 24) who were treated with the 600-mg twice-daily dose of adagrasib, the median number of prior therapies was 4 (range, 1-9).

The ORR was 17% in this cohort, with SD achieved by 78% for a total DCR of 94%. At the time of data cutoff, 67% of the cohort remained on treatment, with 55% on treatment for at least 4 months.

In the other solid tumor cohort of 6 evaluable patients, the median number of prior therapies was 2 (range, 1-5). In this cohort, 2 had appendiceal cancer, 1 had PDAC, and 1 had cholangiocarcinoma. PRs were reported in the patient with cholangiocarcinoma and in the patient with PDAC, and both patients with appendiceal cancer had SD. All patients in this cohort remain on treatment.

Across all patients treated at the recommended phase 2 dose (n = 110), treatment-related AEs of any grade were reported in 85%. The most common treatment-related AEs were nausea (54%), diarrhea (51%), vomiting (35%), fatigue (32%), and increased alanine aminotransferase (20%) and aspartate aminotransferase (17%). Grade 5 treatment-related AEs were reported in 1 patient with recurrent pneumonitis and 1 with cardiac failure. A total of 7.3% of events led to discontinuation.

One cohort of the KRYSTAL-1 study is continuing to look at the combination of adagrasib and cetuximab (Erbitux) in patients with CRC, and a phase 3 trial is planned to continue exploration of this combination.

Targeting KRAS Signaling

Onvansertib Regimen An alternative method of inhibiting KRAS includes targeting synthetic lethal partners of mutant KRAS, which is being explored to overcome the limited activity of the KRAS G12C inhibitors in CRCs specifically. PLK1 is a key regulator of mitosis and is found to be overexpressed in CRC.⁸

In CRC, KRAS-mutant cells were hypersensitive to inhibition of PLK1, which led to exploration of the highly selective PLK1 inhibitor onvansertib (PCM-075) in CRC.

Onvansertib was explored in combination with FOLFIRI (folinic acid, fluorouracil, and irinotecan) plus bevacizumab (Avastin) in patients with previously treated KRAS-mutant metastatic and unresectable CRC in a phase 1b/2 study (NCT03829410). All patients in the study were negative for BRAF V600E mutations and microsatellite instability/mismatch repair deficiency.

Preliminary efficacy from the first 11 evaluable patients in the phase 1b portion, presented in a poster at the ESMO Virtual Congress 2020, showed that PRs were achieved in 45% of patients, and 1 patient went on to receive curative surgery. Durable responses lasting more than 5.5 months (range, 5.5-12) were achieved in 73%, with 36% still on treatment as of the analysis. Just 1 patient progressed within 6 months while on treatment.

The combination was considered to be well tolerated across the doses of onvansertib tested in the study so far. The most common treatment-emergent AEs reported included fatigue in 10 patients, diarrhea in 8, nausea in 8, neutropenia in 8, alopecia in 7, and abdominal or stomach pain in 7. No major or unexpected toxicities reported were attributed to onvansertib.

“Preliminary effectiveness data from the trial [response rate of 45% and DCR of 73%] are impressive and worth further development,” Barzi said.

In May, the agent received a fast track designation from the FDA for the second-line treatment of patients with KRAS-mutant metastatic CRC based on the results of the phase 1b/2 trial.⁹ The trial continues to enroll patients in the phase 2 portion.

Looking Toward 2021 and Beyond

Following the progress of these agents, many other molecules are in development by investigators seeking the most effective way to target KRAS-driven tumors.

For example, the novel molecule BI 1701963 is being explored in a first-in-human trial of patients with KRAS-mutant solid tumors as monotherapy or in combination with trametinib (NCT04111458). The agent is a small molecule inhibitor that prevents the interaction between KRAS and SOS that is used to mediate the exchange between GDP and guanosine triphosphate.

Additionally, new KRAS G12C inhibitors are emerging, including JNJ-74699157 (NCT04006301) and LY3499446 (NCT04165031).

Many of these agents are proceeding to be explored in potential combination regimens for further efficacy with other PAS pathway inhibitors.

Further efficacy with other PAS pathway inhibitors. It will be exciting to see which of these agents come to the forefront in the year(s) ahead.

_References:

_{1. Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19(8):533- 552. doi:10.1038/s41573-020-0068-6}

_{2. Liu P, Wang Y, Li X. Targeting the untargetable KRAS in cancer therapy. Acta Pharm Sin B. 2019;9(5):871-879. doi: 10.1016/j.apsb.2019.03.002}

_{3. Barbacid M. Systematically drugging RAS. Presented at: 32nd EORTCNCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 24-25, 2020; virtual.}

_{4. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548-551. doi:10.1038/nature12796}

_{5. Hong DS, Fakih MG, Strickler JH, et al. KRASG12C Inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207-1217. doi:10.1056/NEJMoa1917239}

_{6. Strickler J, Fakih M, Price TJ, et al. AMG 510, a novel small molecule inhibitor of KRAS G12C, for patients with advanced gastrointestinal tumors: results from the CodeBreak 100 phase 1 trial. Ann Oncol. 2020;31(suppl 3):S226. Abstract 83MO. doi:10.1016/j.annonc.2020.04.039}

_{7. Johnson ML, Ou SHI, Barve M, et al. KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with colorectal cancer (CRC) and other solid tumors harboring a KRAS G12C mutation. Euro J Cancer. 2020;138(suppl 2):S2. doi:10.1016/S0959-8049(20)31077-7}

_{8. Ahn DH, Erlander M, Ridinger M, et al. Phase Ib/II study of the polo-like kinase 1 (PLK1) inhibitor, onvansertib, in combination with FOLFIRI and bevacizumab for second line treatment of KRAS-mutated metastatic colorectal cancer. Ann Oncol. 2020;31(suppl 4):S427. Abstract 436P. doi:10.1016/j.annonc.2020.08.547}

_{9. Cardiff Oncology announces fast track designation granted by the FDA to onvansertib for second-line treatment of KRAS-mutated colorectal cancer. News release. Cardiff Oncology, Inc. May 28, 2020. Accessed November 23, 2020. https://bit.ly/376bPgL}