Chemotherapy-free treatment targeting fusions and driver mutations in KRAS wild-type pancreatic ductal adenocarcinoma, a case series

Abstract

Background: KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established.

Objectives: The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with KRAS-WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients.

Design: We reviewed electronic medical records of patients with KRAS-WT PDAC and advanced disease (n = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315-648 genes for tissue) between years 2015 and 2021.

Methods: Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.

Results: Of 236 PDAC patients, 14 had advanced/metastatic disease with KRAS-WT tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with BRAF alterations, two (14%) with fusions [RET-PCM1 and FGFR2-POC1B (N = 1 each)]; and one with a druggable EGFR (EGFR E746_A755delISERD) variant; two other patients had an STK11 and a MUTYH alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR-altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively.

Conclusion: Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.

Keywords: KRAS protein; case series; molecular targeted therapy; oncogene fusion; pancreatic neoplasms.

Figure 1.

Flow diagram. Foundation Medicine and Tempus are the vendors for the NGS. NGS, next-generation sequencing; PDAC, pancreatic ductal adenocarcinoma.

Figure 2.

Swimmer plot of survival of five patients treated with matched targeted therapy. ¹Blue represents treatments, including matched targeted therapy. Red represents treatments for advanced PDAC, not including matched targeted therapy. ²For the patient with EGFR E746_A755delinsISERD variant, erlotinib was given with gemcitabine for the first 4 months and then switched to erlotinib alone due to emergence of cytopenia for another 7 months. Upon progression, due to emergence of MET amplification, osimertinib plus capmatinib was started, and treatment is ongoing (10+ months). ³For the patient with RET fusion, pralsetinib alone was given for 14 months (progression after 11 months), followed by investigational agent (HSP90 binding molecule to an SN-38 cytotoxic payload) and niraparib (PARP inhibitor) for 4 weeks with fast progression. This was followed by pralsetinib plus cisplatin for 3.5 months.

Figure 3.

OS of five patients treated with matched targeted therapy. (a) OS from the diagnosis of metastatic/advanced disease. For this analysis, patients were left-truncated at the start of targeted therapy. Gray area is the pointwise 95% confidence interval band. (b) OS from the first targeted therapy. Gray area is the pointwise 95% confidence interval band. (c) Survival of PDAC patients in MSK-IMPACT cohort. MSK-IMPACT patient data was retrieved (10,945 patients). Overall, 384 patients with pancreatic adenocarcinoma were selected. Patients were divided by KRAS mutation status into two groups (KRAS-WT = 29, KRAS-mutated = 264). This analysis included all stages (metastatic and non-metastatic) combined. Survival was analyzed. OS was defined as the time between the procedure date when the tumor specimen was collected, and the date of death or last follow-up. While OS is numerically different, the difference was not statistically significant. MSK-IMPACT, memorial sloan kettering integrated mutation profiling of actionable cancer targets; OS, overall survival; PDAC, pancreatic ductal adenocarcinoma.

Figure 4.

Treatment and outcome represented in patient #1 and patient #3. (a) Forty-six-year-old woman with advanced PDAC with ARID1A, CDKN2A, EGFR E746_A755del insISERD, and TP53 alterations on tissue NGS (Table 2 and Supplemental Table 1). She was started on gemcitabine plus erlotinib (EGFR inhibitor) with transition to erlotinib alone due to cytopenia; she attained stable disease for 11 months until progression in the liver (Darker spots in the liver, which were absent in December 2020 scan and emerged in December 2021 scan, are metastatic lesions). (b) In December 2021, osimertinib (EGFR inhibitor) and capmatinib (MET inhibitor) were started, the latter due to MET amplification on liquid biopsy. Repeat CT scans and ctDNA in January 2022 showed partial response with resolution of MET amplification and significant decrease in % cell-free DNA of EGFR from 5.1% to 0.1%. Capmatinib was then held from January to March 2022 because of creatinine elevation. Repeat imaging and ctDNA in March 2022 show rapid progression of tumor in the liver [represented by increase in number and size of dark spots (metastatic lesions) in the liver] and rise in ctDNA upon stopping capmatinib, and rapid response with resumption of capmatinib with ongoing response (May and September 2022 scans show disappearance of the metastatic lesions in the liver). Total duration of EGFR-based targeted therapy is 23+ months at time of data cut-off; total duration of chemotherapy-free EGFR-based targeted therapy is 19+ months. (c) Sixty-four-year-old woman with PDAC and liver metastasis treated with dabrafenib/trametinib in third line due to BRAF ΔN486_P490 in-frame deletion. She has continued partial response at ~18+ months after initiation of matched targeted therapy. Imaging at baseline and last follow-up, along with serial CA19-9, shows the prolonged and deep response. CT, computed tomography; EFGR, epidermal growth factor receptor; MET, MET proto-oncogene, receptor tyrosine kinase; NGS, next-generation sequencing; PDAC, pancreatic ductal adenocarcinoma.