FIGHT: bemarituzumab combined with mFOLFOX6 in first-line for patients with advanced gastric or gastroesophageal junction adenocarcinoma

The FGFR pathway is implicated in the growth and development of malignant cells, and in HER2-negative gastric or gastroesophageal cancers, 30% of patients are found to overexpress FGFR2b.1 Bemarituzumab is a first-in-class humanized IgG1 monoclonal antibody that selectively binds to FGFR2b and recruits NK cells to drive antibody-dependent cell-mediated cytotoxicity.

At this year’s American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, Zev Wainberg, MD of the University of California Los Angeles, Los Angeles, CA, presents the findings of the Phase II FIGHT study (NCT03343301), a global, randomized trial enrolling patients with unresectable, locally advanced or metastatic non-HER2+ gastric cancer whose tumors were found to overexpress FGFR2b.2 Progression-free survival (PFS) was the primary endpoint of this study where patients (n=155) were treated with modified FOLFOX6 and randomized 1:1 to receive 15mg/kg bemarituzumab or placebo until disease progression, intolerable toxicity or death.

The primary endpoint of the study was met with an improved median PFS of 9.5 months in the bemarituzumab arm versus 7.4 months in the placebo arm. The secondary endpoint of overall survival (OS) was also met; the median was not reached in the bemarituzumab arm vs 12.9 months for patients receiving the placebo. In addition, among patients with measurable disease, overall response rate (ORR) improved from 40% in the placebo arm to 53% in the experimental.

 

Grade 3 adverse events were found in 83% of patients in the experimental arm versus 74% in the placebo, with more serious adverse events occurring in 32% and 36% of cases, respectively.

In conclusion, the addition of bemarituzumab to modified FOLFOX6 resulted in clinically meaningful and statistically significant improvements in PFS, OS and ORR, and the findings support further evaluation of this first-in-class agent in patients with gastric cancer.

KEYNOTE-240: Pembrolizumab vs placebo in patients with with advanced hepatocellular carcinoma

The KEYNOTE-240 study3 (NCT02702401) evaluated the use of the anti-PD-1 antibody pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) who were previously treated with sorafenib, a tyrosine kinase inhibitor. Previously reported data did not meet statistical significance criteria for overall survival (OS) and progression-free survival (PFS). At the 2021 ASCO Gastrointestinal Cancers Symposium, Prof. Philippe Merle, MD, PhD of Croix-Rousse Hospital, Lyon, France, updates us on the longer-term data from KEYNOTE-240 after 1.5 years of additional follow up.4

In this Phase III study, patients with advanced HCC who progressed from sorafenib therapy were randomized 2:1 to receive pembrolizumab and best supportive care (n=278) or placebo and best supportive care (n=135). The dual primary endpoints for this investigation were OS and PFS.

After a median of 39.6 months follow-up, median OS was 13.9 months in the pembrolizumab arm and 10.6 months in the placebo arm. Median PFS was 3.3 months for pembrolizumab treated patients and 2.8 months for placebo. As previously reported, adverse events were consistent with the known safety profile of pembrolizumab.

These results suggest that with longer follow-up, the improvement in OS and PFS is maintained over time with pembrolizumab in patients with HCC.

MRD detection with ctDNA from personalized assays in colorectal cancer

The analysis of circulating tumor DNA (ctDNA) represents a non-invasive approach to the detection of resistance mutations resulting in resistance mechanisms, as well as therapeutic and disease monitoring in patients with cancer. Several studies have demonstrated the clinical utility of ctDNA in the detection of minimal residual disease (MRD) in patients with colorectal cancer (CRC) and liquid biopsies have demonstrated accuracy in the stratification of patients who are at a higher risk of recurrence.5

In a U.K. multicenter prospective study6 presented by Dr Gayathri Anandappa, MBBS, MRCP, MPhil, of The Royal Marsden NHS Foundation Trust, London, UK, at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, all patients diagnosed with stage II-III CRC (n=122) had their primary tumors resected which, alongside matched germline DNA, were whole-exosome sequenced for somatic single nucleotide variant (SNV) detection. Paired plasma samples, taken pre- and post-operative treatment, underwent tumor-informed multiplex PCR to identify tumor-specific SNVs.

In patients that had post-operative ctDNA status assessed prior to adjuvant chemotherapy, 13% (14/107) were MRD-positive, and of these patients, 42.9% (6/14) relapsed. In contrast, only 8.6% (8/93) of MRD-negative cases relapsed (HR: 10; 95% CI: 3.3-30; p<0.001).

These results indicate that non-invasive, post-operative ctDNA analysis using a tumor-informed multiplex assay allows for the detection of CRC patients at a higher risk of relapse. In the future, this method of early MRD detection could be used to inform treatment decisions in the clinical setting.

Final results from ClarIDHy: a Phase III study of ivosidenib vs. placebo in previously treated, IDH1-mutated cholangiocarcinoma

Cholangiocarcinoma (CCA) incidence is increasing worldwide7 and there remains a limited selection of effective therapeutic options for these patients. Ivosidenib is a first-in-class, oral, small-molecule inhibitor of mutant IDH1, a genetic alteration present in approximately 20% of intrahepatic CCAs. ClarIDHy8 (NCT02989857) is a global, randomized Phase III study comparing ivosidenib versus placebo in patients with unresectable or metastatic IDH1 gene-mutated CCA. Previously reported data indicated that the primary endpoint was met, with a significant improvement in progression-free survival (PFS) and at this ASCO Gastrointestinal Cancers Symposium 2021, the final results of the study were presented.9

Patients with mutant IDH1 were randomized 2:1 to receive ivosidenib (n=126) or placebo (n=61). Results indicate that median overall survival (OS), as a secondary endpoint of the study, was 10.3 months for patients in the experimental arm and 7.5 months in patients who received the placebo. In the experimental arm, 7% of patients experienced an adverse event that led to treatment discontinuation.

The final results of ClarIDHy suggest that ivosidenib is well tolerated in CCA patients and has a favorable safety profile, and results indicated favorable improvements in OS and PFS, highlighting the clinical benefit of ivosidenib in patients with advanced, IDH1-mutant CCA.

PLANET: pembrolizumab with lanreotide depot for advanced, progressive gastroenteropancreatic neuroendocrine tumors (GEP-NETs)

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are slow-growing, heterogeneous malignancies that arise from diffuse endocrine cells in the gastrointestinal tract or the pancreas. They are relatively uncommon, accounting for 2% of all gastrointestinal malignancies.10 Although surgery remains the foundation of treatment for localized GEP-NETs, systemic treatment options for patients with metastatic NETs have expanded considerably, including the use of somatostatin analogs.

At this years American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, the results of the Phase Ib/II PLANET study (NCT03043664) were presented by Michael Morse, MD, of Duke University Medical Center, Durham, NC, evaluating the use of pembrolizumab with lanreotide depot for patients with advanced, progressive GEP-NETs.11

22 patients with a median of two prior systemic therapies were enrolled. Of the 12 tumors analyzed, 4 had detectable PD-L1 expression and 11 had detectable tumor-infiltrating lymphocytes. A median of 6 pembrolizumab doses (range 2-15) and 7 lanreotide doses (range 2-15) were administered. Six patients experienced treatment-related serious adverse events (abdominal pain, pneumonitis, colitis, and hyperglycemia), all of which were related to pembrolizumab.

 

Median progression-free survival was 5.4 months (95% CI 1.7-8.3 mo) and the combination of lanreotide and pembrolizumab produced stable disease in approximately 40% of patients.

The combination of pembrolizumab and lanreotide in patients with advanced GEP-NETs, a minority of whom had PD-L1 expressing tumors demonstrated 40% disease stability and was not associated with new safety signals.

References

  1. Huang T, Liu D, Wang Y et al. FGFR2 Promotes Gastric Cancer Progression by Inhibiting the Expression of Thrombospondin4 via PI3K-Akt-Mtor Pathway. Cellular Physiology and Biochemistry. 2018;50(4):1332-1345.
  2. Wainberg Z, Enzinger P, Kang Y et al. Randomized double-blind placebo-controlled phase 2 study of bemarituzumab combined with modified FOLFOX6 (mFOLFOX6) in first-line (1L) treatment of advanced gastric/gastroesophageal junction adenocarcinoma (FIGHT). Journal of Clinical Oncology. 2021;39(3_suppl):160-160.
  3. Finn R, Ryoo B, Merle P et al. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. Journal of Clinical Oncology. 2020;38(3):193-202.
  4. Merle P, Edeline J, Bouattour M et al. Pembrolizumab (pembro) vs placebo (pbo) in patients (pts) with advanced hepatocellular carcinoma (aHCC) previously treated with sorafenib: Updated data from the randomized, phase III KEYNOTE-240 study. Journal of Clinical Oncology. 2021;39(3_suppl):268-268.
  5. Reece M, Saluja H, Hollington P et al. The Use of Circulating Tumor DNA to Monitor and Predict Response to Treatment in Colorectal Cancer. Frontiers in Genetics. 2019;10: 1118.
  6. Anandappa G, Starling N, Begum R et al. Minimal residual disease (MRD) detection with circulating tumor DNA (ctDNA) from personalized assays in stage II-III colorectal cancer patients in a U.K. multicenter prospective study (TRACC). Journal of Clinical Oncology. 2021;39(3_suppl):102-102.
  7. Banales J, Marin J, Lamarca A et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nature Reviews Gastroenterology & Hepatology. 2020;17(9):557-588.
  8. Abou-Alfa G, Macarulla T, Javle M et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. The Lancet Oncology. 2020;21(6):796-807.
  9. Zhu A, Macarulla T, Javle M et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. Journal of Clinical Oncology. 2021;39(3_suppl):266-266.
  10. Cives M, Strosberg J. Gastroenteropancreatic Neuroendocrine Tumors. CA: A Cancer Journal for Clinicians. 2018;68(6):471-487.
  11. Morse M, Halperin D, Uronis H et al. Phase Ib/II study of pembrolizumab with lanreotide depot for advanced, progressive gastroenteropancreatic neuroendocrine tumors (PLANET). Journal of Clinical Oncology. 2021;39(3_suppl):369-369.

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