Single-arm, phase 2 study of regorafenib plus nivolumab in patients with mismatch repair-proficient (pMMR)/microsatellite stable (MSS) colorectal cancer (CRC).

Abstract

3560 Background: The role of immunotherapy in the treatment of pMMR/MSS metastatic CRC is not established. A Japanese phase 1b trial in this setting showed the combination of regorafenib (multikinase inhibitor with immunomodulatory activity) plus nivolumab (anti PD-1) had encouraging activity and manageable safety (Fukuoka, 2020). This study further assessed the safety and efficacy of this combination. Methods: Patients (pts) from the US aged ≥18 years who progressed on/were intolerant to standard chemotherapy were enrolled. Regorafenib was given orally, once daily in 28-day (D) cycles (21D on/7D off) plus IV nivolumab 480 mg on D1. Regorafenib starting dose was 80 mg; if well tolerated, it could be escalated to 120 mg in Cycle 2. Primary endpoint was overall response rate (ORR; RECIST 1.1); secondary aims included disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety (NCI-CTCAE v5.0 grade). Biomarker analysis was exploratory. Results: 70 pts (59% male) started treatment. At baseline, median age was 57 years (range 34–85), ECOG PS 0/1 was 51%/49%, 67% had liver metastases (mets), and the primary tumor site was right-sided colon in 36% and rectum in 17%. Median number of cycles was 3.0 (range 1–13); 41% of pts escalated regorafenib to 120 mg. Five pts (7.1%) had a partial response (PR) lasting ≥16 weeks (wks) and 22 (31.4%) had stable disease (SD); pts without liver mets had a higher ORR (21.7%). In pts with tumor samples (n = 40), higher baseline expression (IHC) of cytotoxic T cells (CD3+/CD8+/GranzymeB+), Tregs (FoxP3+), and macrophages (CD68+) trended with clinical benefit (PR/SD ≥16 wks/PFS); pts with liver mets had lower expression. Lower plasma levels of biomarkers of vascular biology (e.g. VEGF-D, Ang-2, VWF) trended with longer PFS. Grade (Gr) 3 treatment-emergent adverse events (TEAEs) occurred in 53% of pts and Gr 4 in 10%. Three pts had a Gr 5 TEAE: n = 1 related to the combination (sepsis); n = 1 related to nivolumab only by investigator (sepsis); n = 1 unrelated to treatment (respiratory failure). Most common Gr 3/4 TEAEs: maculopapular rash (14%), fatigue (7%), pneumonia (6%), increased bilirubin (6%). Conclusions: Combination treatment with regorafenib (up to 120 mg/day) and nivolumab (480 mg every 28D) has manageable safety. Efficacy of this combination in the North American population did not emulate results in the Japanese population. Absence of liver mets and expression of specific biomarkers indicate a better response and may warrant further analysis. Clinical trial information: NCT04126733. [Table: see text]

Clinical management of metastatic colorectal cancer in the era of precision medicine

“…Several clinical studies are investigating the potential role of immune checkpoint inhibitors in combination with chemotherapy, including combinations with antiangiogenic drugs (monoclonal antibodies and multikinase inhibitors); anti-EGFR monoclonal antibodies; inhibitors of intracellular signal-transduction pathways, including KRAS G12C, BRAF V600E, or MEK inhibitors; or radiotherapy. 129,[171][172][173][174][180][181][182][183][184][185][186][187][188][189][190] Although promising signs of therapeutic activity have been observed in some of these studies, further translational and clinical investigation is needed to identify the most effective combination strategies as well to appropriately select the patients who could obtain a clinical benefit from this approach.…”

Exploring immunotherapy in colorectal cancer

“…Following the overexpression of these inhibitory receptors, CD8+ T cells indicates serious dysfunction in cytokine production, proliferation and migration [ 201 ] Liver metastasis Study demonstrated that melanoma patients with liver metastasis response worse than lung metastasis from ICB therapy [ 202 ]. MSS mCRC patients with liver metastasis also cannot benefit from the combination of TKI plus ICB [ 96 , 203 , 204 ] POLD1 DNA Polymerase Delta 1, Catalytic Subunit, DDR: Damage Response and Repair, CDK12 Cyclin-Dependent Kinase 12, SERPINB3/4 Serpin Family B Member 3/4, CMTM6 CKLF like MARVEL Transmembrane Domain Containing 6, STK11 Serine/Threonine Kinase 11, ILC3 Group 3 Innate Lymphoid Cells, Tsens Senescent CD4 + T cells, LDH Lactate Dehydrogenase, NF1 Neurofibromin 1, MET MET Proto-oncogene, Receptor Tyrosine Kinase, DNMT3A DNA Methyltransferase 3 Alpha, DKK1 Dickkopf Wnt Signaling Pathway Inhibitor 1, LAGE3 L Antigen Family Member, 3MET MET Proto-oncogene, Receptor Tyrosine Kinase, DNMT3A DNA Methyltransferase 3 Alpha, DKK1 Dickkopf Wnt Signaling Pathway Inhibitor 1, LAGE3 : L Antigen Family Member 3 …”

“…This study demonstrated an ORR of 28% and a mPFS of 7.8 months (95% CI, 2.8 to NR) in mCRC, with a 1-year PFS rate of 41.7% and a 1-year OS rate of 68.0%, which were considerably higher than the data from previous studies in MSS CRC [ 215 ]. However, this study could not be repeated in the follow-up North American REGONIVO phase II study (NCT04126733), and an ORR of 7.1%, mPFS of 8 weeks, and a mOS of 52 weeks were reported [ 204 ]. The REGOTORI (NCT03946917) study indicated that 5 out of 33 evaluable patients treated with 80 mg regorafenib achieved a tumor response with an ORR of 15.2% (95% CI, 5.7%–32.7%) and a DCR of 36.4% (95% CI, 21.0% to 54.9).…”

Drug Resistance in Colorectal Cancer: From Mechanism to Clinic

“…A combination of regorafenib and nivolumab showed activity in Japanese third-line or later pMMR mCRC with an ORR of 33.3% [ 332 ]. However, this strategy has not been proven effective in the North American population, with an ORR of 7.1% [ 333 ].…”