Starting at the Front Line in Metastatic Pancreatic Cancer As New Options Emerge, How Do You Select and Sequence?

The gastrointestinal cancer experts.

Pancreatic cancers have the dubious distinction of having the lowest survival rates of any major cancer, with an overall 5-year relative survival of only 13%.¹ The majority of pancreatic cancers are detected after they have already spread, with 29% of cases involving regional lymph nodes and 51% of patients receiving a diagnosis of metastatic cancer. Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of pancreatic cancers.² PDAC is particularly resistant to chemotherapy owing to the broad heterogeneity of mutations and dense stromal environment found in these tumors.

Head-to-Head Trials of First-Line Chemotherapy

Both modified FOLFIRINOX (mFFX) and gemcitabine plus nab-paclitaxel (GnP) are preferred first-line regimens for PDAC, according to National Comprehensive Cancer Network (NCCN) guidelines.³ The randomized phase 2 PASS-01 trial (NCT04469556) compared these regimens head-to-head in 140 patients with de novo metastatic PDAC (mPDAC).⁴ Patients given GnP experienced a numerically but not statistically longer progression-free survival (PFS) than did those given FOLFIRINOX (5.5 vs 4.0 months, respectively; P = .14).Median overall survival (OS) was 9.7 months with GnP and 8.4 months with mFFX (P = .04). Partial response (PR) was achieved in 29% of patients receiving GnP and 24% of patients receiving mFFX. Serious adverse events (AEs) were reported in 3% of patients receiving GnP and 13% of patients receiving mFFX.

The phase 3 NAPOLI 3 trial (NCT04083235) compared NALIRIFOX vs GnP in 770 patients with metastatic PDAC.⁵ Median OS with NALIRIFOX therapy was 11.1 months (95% CI, 10.0-12.1 months) vs 9.2 months (95% CI, 8.3-10.6 months) with GnP (HR, 0.83; 95% CI, 0.70-0.99; P = .036). The 12-month OS was 45.6% (95% CI, 40.5%-50.5%) in the NALIRIFOX arm and 39.5% (95% CI, 34.6%-44.4%) in the GnP arm. The 18-month OS was 26.2% (95% CI, 20.9%-31.7%) with NALIRIFOX and 19.3% (95% CI, 14.8%-24.2%) with GnP. Median PFS with NALIRIFOX was 7.4 months vs 5.6 months with GnP (HR, 0.69; 95% CI, 0.58-0.83; P = .0001). Treatment-emergent AEs (TEAEs) were reported in 369 (99.7%) of 370 patients who received NALIRIFOX and 376 (99.2%) of 379 patients who received GnP. The most common TEAEs of grade 3 or 4 with NALIRIFOX and GnP, respectively, were diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%), and neutropenia (14.1% vs 24.5%). Treatment-related AEs (TRAEs) leading to death occurred in 2% of patients in the NALIRIFOX group and 2% of patients in the GnP group.

Targeted Therapies in Early-Phase Trials

The phase 1b/2 OPTIMIZE-1 trial (NCT04888312) evaluated whether adding the anti-CD40 antibody mitazalimab to mFFX would improve outcomes for 70 patients with newly diagnosed PDAC.⁶ Objective responses were confirmed in 23 of 57 patients (40.4%) evaluated for efficacy (1-sided 90% CI; ≥ 32 of 57 patients), including 1 complete response. Median OS was 14.3 months, median PFS was 7.4 months, and median duration of response (DOR) was 12.5 months.⁷ The most commonly reported AEs of grade 3 or greater were consistent with the mFFX safety profile: neutropenia (25.7%), anemia (11.4%), hypokalemia (15.7%), and thrombocytopenia (11.4%). The most common serious AEs reported were vomiting (5%), decreased appetite (6%), diarrhea (4%), and cholangitis (4%).6 None were considered related to mitazalimab.

The phase 1/1b ARC-8 clinical trial (NCT04104672) investigated the benefit of the CD73 inhibitor quemliclustat.⁸ CD73 is overexpressed in 40% to 60% of PDAC and is associated with poor outcomes. ARC-8 combined quemliclustat with GnP with and without the anti–PD-1 antibody zimberelimab in 122 patients with untreated mPDAC. Outcomes were better in the arm without zimberelimab. In the quemliclustat plus GnP arm, the objective response rate (ORR) was 41% (95% CI, 24%-61%), the median PFS was 8.8 months (95% CI, 6.4-12.6 months), and the median OS was 19.4 months (95% CI, 12.1-23.0 months). AEs of grade 3 or greater were reported in 85% of trial participants, with the most common being decreased neutrophil count (31%) and anemia (25%). A total of 23% of patients discontinued the study due to AEs.

For patients with core homologous repair deficiency (HRD) such as germline BRCA1/2 mutations, maintenance olaparib therapy has been shown to improve PFS.⁹ The phase 2 POLAR study (NCT04666740) investigated whether the benefit of this PARP inhibitor combined with pembrolizumab as maintenance therapy could be extended to 30 patients with non–core HRD mutations (cohort B) and exceptional platinum responders (cohort C).¹⁰ The ORR was 0% in cohort B and 13.5% in cohort C. The disease control rate (DCR) was 60% in cohort B and 46.5% in cohort C. The median PFS was 4 months (95% CI, 4-not reached [NR]) in cohort B and 3.3 months (95% CI, 1.9-5.4) in cohort C. Median OS was not reached (95% CI, 12-NR) in cohort B and 11 months (95% CI, 9.1-NR) in cohort C. TRAEs grade 3 and higher were diarrhea (7%), hyperglycemia (7%), anemia (14%), and increased lipase (7%).

Breaking the KRAS Barrier

KRAS mutations occur in approximately 90% of pancreatic cancers, including KRAS G12C mutations in approximately 2%.¹¹ Adagrasib is an irreversible inhibitor of KRAS G12C that was evaluated for efficacy as monotherapy in patients with unresectable or metastatic solid tumors harboring this mutation in the phase 1/2 KRYSTAL-1 trial (NCT03785249). In the 21-patient PDAC cohort, ORR was 33.3%, DCR was 81.0%, median PFS was 5.4 months (95% CI, 3.9-8.2 months), and median OS was 8.0 months (95% CI, 5.2-11.8 months). In all 63 patients in this basket trial, the most common TRAEs were nausea (49.2%), diarrhea (47.6%), fatigue (41.3%), and vomiting (39.7%). Grade 3 TRAEs were reported in 25.4% of patients; grade 4 TRAEs were reported in 1.6%. In the phase 1/2 LOXO-RAS-20001 study (NCT04956640) in patients with solid tumors harboring KRAS G12C mutations, LY3537982 yielded an ORR of 42% in the 12-patient pancreatic cancer cohort.¹²

The ORR was also 42% in 7 patients with pancreatic cancer, including 3 PRs in a phase 1 basket trial of divarasib monotherapy in advanced or metastatic solid tumors harboring a KRAS G12Cmutation.¹³ In the overall population of 137 patients, grade 3 TRAEs were reported in 11% of patients, most commonly diarrhea, increased alanine aminotransferase (ALT) level, and increased aspartate aminotransferase (AST) level. One grade 4 event of anaphylaxis was reported.

Glecirasib produced a confirmed ORR of 46.4%, including 13 PRs and a DCR of 96.4% in 28 patients with PDAC harboring a KRAS G12Cmutation in a phase 1/2 clinical trial (NCT05002270).¹⁴ Median DOR was 4.1 months, and median PFS was 5.5 months (95% CI, 1.2-13.1 months). The most common TRAEs were anemia (52.1%), increased blood bilirubin (39.6%), decreased white blood cell count (18.8%), increased AST (18.8%), diarrhea (16.7%), increased ALT (14.6%), asthenia (14.6%), hypertriglyceridemia (10.4%), and nausea (10.4%). Grade 3 or 4 TRAEs were reported in 25% of patients.

According to NCCN guidelines, germline testing, as well as somatic tumor profiling to look for actionable molecular findings, should be considered for all patients with pancreatic cancer.³ With the advent and advancement of next-generation sequencing technology, molecularly informed treatment selection and sequencing is at the forefront of the field.

References

1. Cancer stat facts: pancreatic cancer. National Cancer Institute. Accessed July 17, 2024. https://seer.cancer.gov/statfacts/html/pancreas.html
2. Adamska A, Domenichini A, Falasca M. Pancreatic ductal adenocarcinoma: current and evolving therapies. Int J Mol Sci. 2017;18(7):1338. doi:10.3390/ijms18071338
3. NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 2.2024. Updated April 30, 2024. Accessed July 19, 2024. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
4. Knox JJ, Jaffee EM, O’Kane GM, et al. Early results of the PASS-01 trial: pancreatic adenocarcinoma signature stratification for treatment-01. J Clin Oncol. 2024;42(suppl 17):LBA4004. doi:10.1200/JCO.2024.42.17_suppl.LBA4004
5. Wainberg ZA, Melisi D, Macarulla T, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet. 2023;402(10409):1272-1281. doi:10.1016/S0140-6736(23)01366-1
6. Van Laethem JL, Borbath I, Prenen H, et al. Combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (OPTIMIZE-1): a single-arm, multicentre phase 1b/2 study. Lancet Oncol. 2024;25(7):853-864. doi:10.1016/S1470-2045(24)00263-8
7. Laethem J-LV, Borbath I, Geboes KP, et al. OPTIMIZE-1 primary analysis: safety, efficacy and biomarker results of a phase 1b/2 study combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC). J Clin Oncol. 2024;42(suppl 16):4133. doi:10.1200/JCO.2024.42.16_suppl.4133
8. Wainberg ZA, Manji GA, Bahary N, et al. ARC-8: phase 1/1b randomized study of quemliclustat +gemcitabine/nab-paclitaxel ± zimberelimab in patients with treatment-naive metastatic pancreatic adenocarcinoma. J Clin Oncol. 2024;42(suppl 3):665. doi:10.1200/JCO.2024.42.3_suppl.665
9. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317-327. doi:10.1056/NEJMoa1903387
10. Park W, O’Connor C, Chou JF, et al. Phase 2 trial of pembrolizumab and olaparib (POLAR) maintenance for patients (pts) with metastatic pancreatic cancer (mPDAC): two cohorts B non-core homologous recombination deficiency (HRD) and C exceptional response to platinum-therapy. J Clin Oncol. 2023;41(suppl 16):4140. doi:10.1200/JCO.2023.41.16_suppl.4140
11. Pant S, Yaeger R, Spira AI, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41(suppl 36):425082. doi:10.1200/JCO.2023.41.36_suppl.425082
12. Murciano-Goroff YR, Heist RS, Kuboki Y, et al. A first-in-human phase 1 study of LY3537982, a highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C-mutant advanced solid tumors. Presented at: 2023 American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando, FL.
13. Sacher A, LoRusso P, Patel MR, et al; GO42144 Investigator and Study Group. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N Engl J Med. 2023;389(8):710-721. doi:10.1056/NEJMoa2303810
14. Li J, Shen L, Gu Y, et al. Preliminary activity and safety results of KRAS G12C inhibitor glecirasib (JAB-21822) in patients with pancreatic cancer and other solid tumors. J Clin Oncol. 2024;42(suppl 3):604. doi:10.1200/JCO.2024.42.3_suppl.604

LEARNING OBJECTIVES

Upon successful completion of this activity, you should be better prepared to:

• Select appropriate first-line therapy for locally advanced or metastatic pancreatic cancer based on relevant biomarkers, clinical, and logistical factors.

• Develop an evidence-based strategy for the treatment of metastatic pancreatic cancer in patients who experience disease progression on front-line chemotherapy, exploring the importance of age, performance status, and prior therapy exposure

• Explain the biologic rationale and clinical data for investigational agents currently being evaluated in pancreatic cancer

• Identify a plan to recognize and manage adverse effects associated with approved systemic regimens commonly employed in the management of pancreatic cancer to support quality of life and continuation of therapy

RELEASE DATE: September 1, 2024
EXPIRATION DATE: September 1, 2025

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