Phase II Single-Arm Study of Palbociclib and Cetuximab Rechallenge in Patients with KRAS/NRAS/BRAF Wild-Type Colorectal Cancer
Jonathan D Sorah, Dominic T Moore, Matthew J Reilley, Mohamed E Salem, Tammy Triglianos, Hanna K Sanoff, Autumn J McRee, Michael S Lee, Jonathan D Sorah, Dominic T Moore, Matthew J Reilley, Mohamed E Salem, Tammy Triglianos, Hanna K Sanoff, Autumn J McRee, Michael S Lee
Abstract
Background: Cetuximab is often administered to patients with KRAS wild-type (KRAS-WT) metastatic colorectal cancer (mCRC), although resistance inevitably develops. We hypothesized that co-inhibition of the epidermal growth factor receptor (EGFR) with cetuximab and downstream cyclin-dependent kinases (CDK) 4/6 with palbociclib would be effective for anti-EGFR rechallenge in KRAS-WT mCRC.
Methods: We designed a single-arm, Simon's 2-stage, phase II trial of cetuximab and palbociclib in KRAS-WT mCRC treated with ≥2 prior lines of therapy. We report here on cohort B rechallenging patients with anti-EGFR-based therapy who had disease control of at least 4 months on prior anti-EGFR therapy. Primary endpoint was disease control rate (DCR) at 4 months.
Results: Ten evaluable patients were enrolled in this cohort. The 4-month DCR was 20%, which did not fulfill the prespecified 4-month DCR rate to continue. Median progression-free survival was 1.8 months and median overall survival was 6.6 months. Three patients had stable disease, although overall response rate was 0%. Most common treatment-related grades 3-4 adverse events were lymphopenia and leukopenia.
Conclusion: Selection of patients for anti-EGFR rechallenge using clinical criteria alone was insufficient to identify response to palbociclib + cetuximab. Additional biomarkers are needed to select anti-EGFR rechallenge and circulating tumor DNA (ctDNA) analysis is planned for samples collected in this study. (ClinicalTrials.gov Identifier: NCT03446157).
Keywords: KRAS wild type; anti-EGFR therapy; cetuximab; colorectal cancer; palbociclib.
Conflict of interest statement
Tammy Triglianos: Pfizer (C/A); Hanna K Sanoff: AstraZeneca, F. Hoffman La Roche, Amgen, Bristol-Myers Squibb, Pfizer, BioMed Valley Discoveries, Regenix, Exelixis (RF [institution]); Autumn J McRee: Biomed Valley Discoveries, Merck, Eli Lilly (RF), Merck (SAB), Janssen (E); Michael S. Lee: Imvax, G1 Therapeutics, Delcath, Pfizer (C/A); Repare, Arcus Bioscience, Merck, Erasca, Shanghai EpimAb (RF). The other authors indicated no financial relationships. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board.
© The Author(s) 2022. Published by Oxford University Press.
Figures
References
- Karapetis CS, Khambata-Ford S, Jonker DJ, et al. . K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757-1765. 10.1056/NEJMoa0804385.
- Misale S, Arena S, Lamba S, et al. . Blockade of EGFR and MEK intercepts heterogenous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer. Sci Transl Med. 2014;6(224):224-226.
- Misale S, Nicolantonio FD, Sartore-Bianchi A, et al. . Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov. 2014;4(11):1269-1280.
- Santini D, Vincenzi B, Addeo R, et al. . Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away form acquired resistance?. Ann Oncol. 2012;23(9):2313-2318. 10.1093/annonc/mdr623.
- Strickler JH, Loree JM, Ahronian LG, et al. . Genomic landscape of cell-free DNA in patients with colorectal cancer. Cancer Discov 2018;8(2):164-173. 10.1158/-17-1009.
- Siravegna G, Mussolin B, Buscarino M, et al. . Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 2015;21(7):795-801. 10.1038/nm.3870.
- Morelli MP, Overman MJ, Dasari A, et al. . Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. Ann Oncol. 2015;26(4):731-736. 10.1093/annonc/mdv005.
- Cremolini C, Rossini D, Dell’Aquila E, et al. . Rechallenge for patients with RAS and BRAF wild-type metastatic colorectal cancer with acquired resistance to first-line cetuximab and irinotecan: a phase 2 single-arm clinical trial. JAMA Oncol. 2019;5(3):343-350. .
- Martinelli E, Martini G, Famiglietti V, et al. . Cetuximab rechallenge plus avelumab in pretreated patients with RAS wild-type metastatic colorectal cancer: the phase 2 single-arm clinical CAVE trial. JAMA Oncol. 2021;7(10):15291529. 10.1001/jamaoncol.2021.2915.
- Sartore-Bianchi A, Pietrantonio F, Lonardi Set al. Phase II study of anti-EGFR rechallenge therapy with panitumumab driven by circulating tumor DNA molecular selection in metastatic colorectal cancer: the CHRONOS trial. Meeting Abstract ASCO Annual Meeting 2021.
- Global Cancer Observatory. International Agency for Research on Cancer. World Health Organization. .
- Price TJ, Peeters M, Kim TW, et al. . Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): an randomized, muticentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014;15(6):569-579. 10.1016/S1470-2045(14)70118-4.
- The Cancer Genome Atlas.
- Lee MS, Hems TL, Feng N, et al. . Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models. Oncotarget. 2016;7(26):39595-39608.
- Kwong LN, Costello JC, Liu H, et al. . Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med. 2012;18(10):15032941.-150321510. 10.1038/nm.2941.
- Willobee BA, Gaidarski AA, Dosch AR, et al. . Combined blockade of MEK and CDK4/6 pathways induces senescence to improve survival in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2021;20(7).
- Zhou J, Wu Z, Wong G, et al. . CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma. Nat Commun. 2017;8:13897. 10.1038/ncomms13897.
- Michel L, Ley J, Wildes T, et al. . Phase I trial of palbocilcib, a selective cyclin dependent kinase 4/6 inhibitor, in combination with cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma. Oral Oncol. 2016;58:41-48.
- Parseghian CM, Loree JM, Morris VK, et al. . Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge. Ann Oncol. 2019;30(2):243-249.
Source: PubMed