The efficacy of each combination therapy targeting KRAS will likely depend on the tumor lineage, said Gordon Mills, MD, PhD.
Gordon Mills, MD, PhD
Targeting component of signal transduction pathways associated with KRAS may be the long-awaited solution for management of certain cancers harboring KRAS mutations, once considered an undruggable target, according to promising results from early-stage clinical trials. However, the efficacy of each combination therapy will likely depend on the tumor lineage, Gordon Mills, MD, PhD, told Targeted Therapies in Oncology in an interview.
KRAS mutations are common in multiple types of cancer, including colorectal cancer (CRC), non–small cell lung cancer (NSCLC), low-grade serous ovarian cancer (LGSOC), endometrial cancer, and pancreatic cancer. Although one drug (AMG 510) has shown early promise in targeting advanced cancers with the KRAS G12C mutation,1 efforts to directly target other KRAS mutations have been largely unsuccessful. Mills suggested that the multiple functions of the mutation likely contribute to the difficulty of directly targeting the kinase.
“KRAS is not only a proliferation inducer, it is also a potent mediator of resistance to apoptosis and other mechanisms of cell death,” Mills, who is director of precision oncology at the Knight Cancer Institute and a professor of cell, developmental, and cancer biology at the School of Medicine, both of Oregon Health & Science University in Portland, said when discussing current research. “You have cells that are primed to remain viable under therapeutic stress, [which may be] why targeting RAS-mutant tumors has been harder than expected.”
Using drug combinations to target proteins that indirectly interact with KRAS has emerged as a promising alternative methodology. Mills said that these types of multitargeted approaches will likely be necessary to achieve a durable therapeutic response in most cancers harboring mutant KRAS.
“The expectation that you’re going to see marked activity of a monotherapy in a KRAS-mutant tumor is naive,” he said. “These are aggressive tumors [that are] difficult to treat.”
A meta-analysis showed that upregulation of Pololike kinase 1 (PLK1)—a serine/threonine kinase that regulates mitotic progression2—in CRC was associated with poorer overall survival, lymph node metastasis, and more advanced disease stages.3 In another study, a genome-wide RNA interference screen identified PLK1 as having synthetic lethal interactions with the KRAS oncogene. The authors showed that KRAS-mutant CRC cells were more sensitive to PLK1 inhibition than KRAS–wild-type cells; the former cells arrested in prometaphase, accumulated, and subsequently died.4
Onvansertib (NMS-P937) is an oral, highly selective ATP-competitive inhibitor of PLK1. Its specificity for PLK1 may improve its long-term safety profile over other PLK inhibitors that also target the PLK2 and PLK3 isoforms.2 A preclinical study showed that onvansertib had antiproliferative effects in multiple cell lines derived from hematologic and solid malignancies, including CRC, and the mechanism of action was determined to be induction of mitotic cell cycle arrest followed by apoptosis. In mice implanted with HT29 human colon adenocarcinoma xenografts, the combination of onvansertib and irinotecan led to greater tumor regression than either drug alone.2
These preclinical findings supported the rationale for adding onvansertib to standard-of-care second-line therapy—chemotherapy combination folinic acid (leucovorin), fluorouracil, and irinotecan (FOLFIRI) plus bevacizumab (Avastin)—in KRAS-mutated metastatic CRC. Results from a phase 1b/2 trial (NCT03829410) presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in January showed that 5 of 5 evaluable patients with metastatic KRAS-mutant disease had tumor regression at 8 and 16 weeks after starting therapy with onvansertib plus FOLFIRI/bevacizumab, with responses observed across several KRAS mutations. At 16 weeks, tumor shrinkage greater than 25% was observed in 3 of the 5 patients, 1 of whom became eligible for curative surgery.5
More recently, updated results presented at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting I showed a partial response (PR) or stable disease (SD) in 7 of 8 evaluable patients. Prior research had found that a decrease in KRAS-mutant circulating tumor DNA (ctDNA) measured in the plasma was an early marker of therapeutic response. Consistent with this, 5 patients had a decrease in KRAS-mutant ctDNA to nondetectable levels in the first treatment cycle (28 days), and all of these patients had tumor regression at 8 weeks.6
Gain-of-function KRAS mutations found in cancer keep KRAS in a persistently active state; this leads to deregulated MAPK pathway signaling via the downstream RAF/MEK/ERK components (FIGURE).7 The MAPK pathway plays roles in cell survival, cell cycle progression, and differentiation. MEK1/2 is frequently studied as an optimal therapeutic target in this pathway because of its narrow substrate specificity; inhibiting MEK1/2 blocks ERK1/2 activity without affecting other signaling pathways.8 VS-6766 (also known as CH5126766, CKI27, and RO5126766) inhibits the MAPK signaling pathway by blocking the kinase activity of MEK and the ability of RAF to phosphorylate MEK, which prevents compensatory activation of MEK.9
However, activation of focal adhesion kinase, or FAK, has been shown to be a possible mechanism of resistance to MEK inhibition. FAK is overexpressed in multiple advanced-stage cancers and promotes tumor progression and metastasis through effects on cancer cells and stromal cells in the tumor microenvironment.10 In preclinical studies, suppression of FAK induced cell death in xenograft and transgenic models of KRAS-mutant lung adenocarcinoma,11 and concomitant inhibition of FAK and RAF/MEK in vitro provided synergistic antitumor effects.9
Interim results of an ongoing phase 1 trial (FRAME; NCT03875820) presented at the 2020 AACR Virtual Annual Meeting I showed that a combination of VS-6766 and the FAK inhibitor defactinib demonstrated early signs of clinical activity in patients with advanced cancers harboring a KRAS mutation.12 Responses were observed in 4 of 6 patients with KRAS-mutant LGSOC, 3 of whom had had prior exposure to a MEK inhibitor. Responses were durable, with a median time on treatment of 20.5 months. Although responses were less robust and durable in the 10 patients with KRAS-mutant NSCLC, a PR was observed in 1 patient and disease control was observed in 8, with a median time on treatment of approximately 18 weeks.
After observing relatively high response rates among patients with the KRAS G12V mutation in the above study, the investigators performed a combined analysis that included data from that trial and a previously published single-agent study of VS-6766 whose results were presented in 2017 at the ASCO Annual Meeting (NCT02407509).12 This combined analysis showed an overall response rate (ORR) of 57% in patients with KRAS G12V–mutant NSCLC, including 2 of 5 patients on single-agent VS-6766 and 2 of 2 patients who received the combination of VS-6766 and defactinib.8 In patients with KRAS G12V–mutant gynecologic cancers, the ORR was 60% (1 of 2 patients on single-agent VS-6766 and 2 of 3 patients on combination therapy).
Mills noted that lineage-specific events affect the function and mechanism of action of KRAS and may partly explain why the efficacy and durability of therapeutic combinations vary among different types of KRAS-mutant cancers, as was observed with LGSOC and NSCLC. “Co-mutations, other aberrations, and lineage-specific gene expression patterns all condition the effects of targeted therapies,” he said.
The unique structure of MEK is advantageous for the design of ATP-noncompetitive inhibitors such as binimetinib (Mektovi); their binding site has a low degree of sequence homology, producing selectivity for MEK1/2. In contrast, ATP-competitive MEK inhibitors have a binding site, the ATP-binding pocket, that is highly homologous among multiple protein kinases; this leads to inadvertent multikinase inhibition and associated toxicity.8
Despite this advantage, the phase 3 MILO/ ENGOT-ov11 trial (NCT01849874), which compared binimetinib to physician’s choice of chemotherapy in patients with LGSOC, was terminated after the interim analysis showed no difference in median progression-free survival (PFS; 9.1 months vs 10.6 months with chemotherapy; HR, 1.21; 95% CI, 0.79-1.86) or ORR (16% vs 13%).14 A post hoc molecular analysis showed that the median PFS was significantly longer for patients with KRAS mutations (17.7 months vs 10.8 months for patients with KRAS–wild-type tumors; P = .006), suggesting that KRAS mutation status may predict benefit from binimetinib.15 However, whether KRAS status alone should guide the decision to use a MEK1/2 inhibitor is unclear. A phase 2/3 study (NCT02101788) showed that the MEK inhibitor trametinib (Mekinist) was associated with longer PFS and duration of response than physician’s choice of chemotherapy in women with recurrent or progressive LGSOC or peritoneal cancer. These results led the investigators to conclude that trametinib has the potential to represent a new standard of care in the treated patient population, which was a biomarker unselected group.16
The RAF kinases (ARAF, BRAF, and CRAF) are activated by KRAS in the MAPK signaling pathway, and BRAF mutations are a common therapeutic target due to their high frequency in solid malignancies such as melanoma and CRC. BRAF inhibitors vemurafenib (Zelboraf) and dabrafenib (Tafinlar) have demonstrated strong clinical activity in BRAF V600E–mutated melanoma, but their relatively weak efficacy in other BRAF-mutant tumors, such as CRC, may be related to EGFR-mediated reactivation of the MAPK signaling pathway through a feedback activation mechanism.17 Combining EGFR and BRAF inhibitors led to better efficacy in preclinical models than either agent alone, suggesting that inhibiting both enzymes may improve clinical efficacy across a wider range of tumors with abnormal MAPK pathway activation.17
Lifirafenib (BGB-283) is a novel, first-in-class inhibitor of wild-type ARAF, BRAF, and CRAF; BRAF V600E; and wild-type EGFR and KRAS that showed strong efficacy in xenograft models of BRAF V600E–mutated CRC.18,19 A phase 1 trial (NCT02610361) was designed to evaluate the safety, pharmacokinetics, maximum tolerated dose, and preliminary antitumor activity in patients with KRAS/NRAS- or BRAF-mutant tumors.18 Among the 59 patients with KRAS mutations, PRs were observed in 2 (1 with endometrial cancer and 1 with codon 12–mutated NSCLC) and SD was observed in 32, including 5 with endometrial cancer and 2 with NSCLC.18 The authors also noted that although prolonged disease control was observed in NSCLC and endometrial cancer, the clinical activity of lifirafenib appeared to be more limited in KRAS-mutated CRC and pancreatic cancer, supporting the premise that oncogenic KRAS is context dependent and requires different treatment approaches based on tumor type.
In addition to drugs that target KRAS-associated proteins, multiple other types of therapeutics have been combined with MEK inhibitors to treat KRAS-mutant cancers, with promising results from ongoing early-stage clinical trials. A phase 1/2 trial (NCT03162627) is examining selumetinib (a MEK1/2 inhibitor) plus the PARP inhibitor olaparib (Lynparza) in solid tumors with RAS pathway alterations and ovarian tumors with PARP resistance. Additionally, pembrolizumab (Keytruda) and trametinib in KRAS-mutated stage IV NSCLC are being examined in a phase 1 trial (NCT03299088).
“There is a lot of excitement out there right now about KRAS-mutant tumors,” said Mills. “We are doing far better than we were a couple of years ago.”
However, Mills stated that applying effective strategies to treat KRAS-mutated pancreatic cancer remains a key challenge moving forward. KRAS mutations are common in this type of cancer and the long-term efficacy of currently approved therapies is limited.
“KRAS mutations are clearly contextual in what they do, and what happens in some tumor types, such as endometrial and low-grade serous ovarian cancers, is very different from what we see in pancreatic cancer,” said Mills. “We should not immediately say that the poor outcomes in pancreatic cancer are due to KRAS [mutations] but rather KRAS [mutations] in the context of it being a pancreatic cancer.”
1. Govindan R, Fakih MG, Price TJ, et al. Phase 1 study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumors. Ann Oncol. 2019;30(suppl 5):v159-v193. doi:10.1093/annonc/mdz244
2. Valsasina B, Beria I, Alli C, et al. NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies. Mol Cancer Ther. 2012;11(4):1006-1016. doi:10.1158/1535-7163.MCT-11-0765
3. Ran Z, Chen W, Shang J, et al. Clinicopathological and prognostic implications of Polo-like kinase 1 expression in colorectal cancer: a systematic review and meta-analysis. Gene. 2019;721:144097. doi:10.1016/j. gene.2019.144097
4. Luo J, Emanuele MJ, Li D, et al. A genome-wide RNAi screen identif ies multiple synthetic lethal interactions with the Ras oncogene. Cell. 2009;137(5):835‐848. doi:10.1016/j.cell.2009.05.006
5. Lenz HJ, Ahn DH, Ridinger M, Erlander MG, Barzi A. A phase Ib/II study of onvansertib (PCM-075) in combination with FOLFIRI and bevacizumab for second-line treatment of metastatic colorectal cancer (mCRC) in patients with a KRAS mutation. J Clin Oncol. 2020;38(suppl 4). doi:10.1200/ JCO.2020.38.4_suppl.TPS265
6. Barzi A, Lenz HJ, Samuëlsz E, et al. A phase 1b/2 study of onvansertib in combination with FOLFIRI and bevacizumab for second-line treatment of metastatic colorectal cancer in patients with a KRAS mutation. Presented at: 2020 AACR Virtual Annual Meeting I; April 27-28, 2020. https://bit. ly/3eyajGH
7. 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
8. Ohren JF, Chen H, Pavlovsky A, et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol. 2004;11(12):1192-1197. doi:10.1038/nsmb859
9. Verastem Oncology announces preliminary data from investigator-initiated study highlighting clinical activity of RAF/MEK and FAK combination in KRAS mutant tumors presented at the American Association for Cancer Research 2020 Virtual Annual Meeting I. News release. Business Wire; April 27, 2020. Accessed June 26, 2020. bwnews.pr/35gGVRh
10. Sulzmaier FJ, Jean C, Schlaepfer DD. FAK in cancer: mechanistic f indings and clinical applications. Nat Rev Cancer. 2014;14(9):598-610. doi:10.1038/nrc3792
11. Konstantinidou G, Ramadori G, Torti F, et al. RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. Cancer Discov. 2013;3(4):444-457. doi:10.1158/2159-8290.CD-12-0388
12. Shinde R, Terbuch A, Little M, et al. Phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers. Presented at: 2020 AACR Virtual Annual Meeting I; April 27-28, 2020. Abstract CT143
13. Chenard-Poirier M, Kaiser M, Boyd K, et al. Results from the biomarker-driven basket trial of RO5126766 (CH5127566), a potent RAF/MEK inhibitor, in RAS- or RAF-mutated malignancies including multiple myeloma. J Clin Oncol. 2017;35(suppl 15):2506. doi:10.1200/JCO.2017.35.15_suppl.2506
14. Grisham R, Monk JB, Banerjee S, et al. 1 MILO/ENGOT-OV11: phase-3 study of binimetinib versus physician’s choice chemotherapy (PCC) in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. Int J Gynecol Cancer. 2019;29(suppl 3):A1. doi:10.1136/ijgc-2019-IGCS.1
15. Grisham R. MILO/ENGOT-ov11: phase-3 study of binimetinib versus physician's choice chemotherapy in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. Presented at: 2020 Society for Gynecologic Oncology Annual Meeting on Women’s Cancer; March 28-31, 2020. Accessed June 26, 2020. https://bit.ly/2ATeCxs
16. Gershenson DM, Miller A, Brady W, et al. A randomized phase II/III study to assess the efficacy of trametinib in patients with recurrent or progressive low-grade serous ovarian or peritoneal cancer. Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394
17. Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2(3):227‐235. doi:10.1158/2159-8290.CD-11-0341
18. Desai J, Gan H, Barrow C, et al. Phase I, open-label, dose-escalation/ dose-expansion study of lifirafenib (BGB-283), an RAF family kinase inhibitor, in patients with solid tumors. J Clin Oncol. Published online March 17, 2020. doi:10.1200/JCO.19.02654
19. Tang Z, Yuan X, Du R, et al. BGB-283, a novel RAF kinase and EGFR inhibitor, displays potent antitumor activity in BRAF-mutated colorectal cancers. Mol Cancer Ther. 2015;14(10):2187-2197. doi:10.1158/15357163.MCT-15-0262
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