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Abstract

Pancreatic cancer is a rising cause of cancer death. Therapeutic options are scarce and of limited efficacy. Up to 26% of patients with metastatic pancreatic cancer could benefit from targeted therapies. We report here for the first time the case of three patients with metastatic pancreatic ductal adenocarcinoma (PDAC) without KRAS alteration for whom an activating mutation in exon 19 of the epidermal growth factor receptor (EGFR) gene was found through mainstreaming NGS. The EGFR variant was confirmed on multiple tumor samples and by circulating tumor DNA (ctDNA) analysis in two patients. The three patients were treated with osimertinib with early molecular, biologic, and morpho-metabolic responses. At the last follow-up, one patient had an ongoing response after 17 months, and disease control had been maintained for 8 and 6 months in the other two. Known resistance mechanisms were observed on ctDNA analysis at progression. These observations demonstrate the benefit of osimertinib for treating EGFR-mutated PDAC and highlight the interest in investigating rare molecular alterations, especially in patients without KRAS alterations.

Plain language summary

Three patients with metastatic pancreatic cancers with a rare genetic alteration respond durably to a targeted therapy

Pancreatic cancer is a rising cause of cancer death. It could become the second cause of cancer-related mortality in western countries by 2030. Therapeutic options are scarce and of limited efficacy. Some patients could benefit from therapies targeting specific alterations. We report here for the first time the case of three patients with metastatic pancreatic cancers treated by a drug called osimertinib. This drug specifically targets a mutation activating cellular growth pathways. This mutation was present among the three patients. It was found through modern techniques of sequencing on solid and liquid biopsies. The three patients were treated with osimertinib with early responses. At last follow up, one patient had ongoing response after 17 months. The cancers of the other two had been controlled for 8 and 6 months. For the two patients who had progression of their pancreatic cancer, already described mutations conferring resistance to osimertinib were found. These observations demonstrate the benefit of osimertinib for the treatment of EGFR-mutated pancreatic cancer. It highlights the interest of investigating rare molecular alterations, especially in a subgroup of patients without KRAS mutations among which other targetable alterations have been investigated.

Keywords

case report ctDNA EGFR exon 19 deletion KRAS wild type liquid biopsy NGS osimertinib pancreatic cancer pancreatic ductal adenocarcinoma

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of pancreatic cancer. PDAC incidence is rising and it is expected to become the second cause of cancer-related mortality in Western countries by 2030.¹ Prognosis of advanced PDAC is very poor with a median survival inferior to 12 months.^2,3

Standard treatment is still based on multi-drug chemotherapy regimens including 5-fluorouracil (5-FU), irinotecan, oxaliplatin, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel. Second-line treatment options have limited efficacy with median progression-free survival (PFS) between 3 and 4 months.^4,5 The genomic landscape of PDAC is complex with the most frequent mutations found in KRAS (85%–90% of cases), TP53, CDKN2A, and SMAD4. Targeted therapies are lacking for most of the patients but new therapeutic options have shown efficacy in rare molecular subgroups: immune checkpoint inhibitors in MicroSatellite Instability (MSI)/ deficient MisMatch Repair (dMMR) PDAC (1% frequency),⁶ olaparib maintenance for BRCA1/2 germline-mutated patients (5%–7% frequency),⁷ specific kinase inhibitors for NTRK and NRG1 fusion genes (1% frequency each),^5,8 and sotorasib and adagrasib for KRAS G12C-mutated PDAC (1%–2% frequency⁹). Altogether, up to 26% of patients with PDAC could harbor actionable mutations, with a retrospective analysis showing prolonged overall survival for patients receiving matched targeted therapies.¹⁰

EGFR exon 19 activating mutations are rare (<1%) in PDAC with only a small number of clinical cases reported.^11–18 Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) whose superiority over first-generation TKI erlotinib for EGFR exon 19 activating mutations in non-small-cell lung cancer (NSCLC) has recently been demonstrated.^19,20

We describe here for the first time the rapid and prolonged clinical efficacy of osimertinib in three patients with advanced PDAC harboring EGFR exon 19 variant, with circulating tumor DNA (ctDNA) dynamic analyses and biologic and morpho-metabolic evaluations. We also performed a systematic literature review of EGFR exon 19 altered PDAC treated with targeted therapies.

The reporting of this study conforms to the CARE guidelines (Supplemental Table 1).²¹

Cases summary

Patient 1

A 46-year-old woman developed diabetes mellitus in September 2020. A 17 kg weight loss and epigastric pain led to the discovery of a CT scan in July 2021 of a pancreatic body mass associated with hepatic lesions. A liver nodule biopsy found a mild-differentiated adenocarcinoma with an immunohistochemistry (IHC) profile compatible with a PDAC (TTF1−, CDX2+, CK7+, CK20+). An 18F-FDG positron emission tomography (18F-FDG PET) showed lymph node and pulmonary metastases. A first-line treatment by FOLFIRINOX was initiated in August 2021. CT scan showed partial response (PR) after eight cycles. LV5FU2 was continued for 8 months. A CT scan in August 2022 showed unequivocal progression leading to the restart of FOLFIRINOX for 6 months, with a 48% decrease in tumor size as the best response. CT scan revealed in February 2023 pancreatic, hepatic, and lymph-node progression. Gemcitabine/nab-paclitaxel was therefore started in March 2023. After two cycles, the patient presented with jaundice and the CT scan showed progression. A metallic-covered stent was put through endoscopic retrograde cholangiopancreatography.

Molecular analysis on the first liver nodule biopsy was performed by NGS AmpliSeq™ for Illumina^® Focus Panel covering 52 genes of interest to find actionable alterations. The analysis revealed a KRAS wild-type (WT)/EGFR-activating exon 19 deletion: EGFR(NM_005228.5):c.2237_2255delinsT, p.(Glu746_Ser752delinsVal) with a variant allele frequency (VAF) of 72%. An amplification of the EGFR gene was also found, along with two other pathogenic variants: TP53(NM_000546.6): c.988del, p.(Leu330PhefsTer15) (VAF of 54%) and CDKN2A(NM_000077.5):c.242_252del, p.(Pro81ArgfsTer35) (VAF of 46%). The EGFR variant was confirmed by a new liver biopsy in May 2023 (VAF of 70%) and by June 2023 liquid biopsy (VAF of 64%). After discussion in a molecular multidisciplinary meeting and informed patient agreement, osimertinib (80 mg per day) was started in June 2023.

An 18F-FDG PET showed at 1 month a notable metabolic response of nearly all lesions (Figure 1(a)), with stable disease (SD) per RECIST on a CT scan in August 2023 (−16%). Both biological and molecular responses were obtained (Figure 2(a)) with a new panel sequencing on ctDNA at 2 weeks showing a VAF of the EGFR variant reduced to 0.8% (with no other associated alterations detected). Digestive toxicity (grade 2 diarrhea) required treatment discontinuation and then dose reduction to 40 mg per day. A progressive elevation of CA 19.9 in August 2023 was associated with a plasmatic residual concentration of osimertinib under the recommended therapeutic concentrations. Therefore, osimertinib 80 mg per day was restarted with biological efficacy (Figure 2(a)) and manageable grade 1 diarrhea. SD (−21%) was maintained on a CT scan in October 2023. In December 2023, radiological and biological (Figure 1(a)) progression occurred, then confirmed by ctDNA analysis showing the VAF of the EGFR variant increased to 81% associated with EGFR gene amplification and the known TP53 and CDKN2A variants described above (VAF of 52% and 49%, respectively). Interestingly, known resistance mechanisms to EGFR-TKIs in lung cancer had emerged: MET gene amplification and two resistance point mutations to osimertinib: EGFR(NM_005228.5):c.2390G>C, p.(Cys797Ser) (VAF of 1.4%) and EGFR(NM_005228.5):c.2170G>A, p.(Gly724Ser) (VAF of 1.4%). The patient died in January 2024.

Figure 1.

Metabolic responses to osimertinib showed by 18F-FDG positron emission tomographies (18F-FDG PET) realized before and after 2 weeks of treatment. (a) Patient 1: hepatic metastases showed nearly complete morpho-metabolic responses. (b) Patient 2: cervical lymph nodes and hepatic metastases showed morpho-metabolic responses.

Figure 2.

Evolution of CA 19.9 and the VAF of EGFR exon 19 activating mutation (for (a) and (b) only) over time and under treatment. (a) Patient 1: 1_osimertinib 80 mg per day; 2_10-day stop and dose reduction at 40 mg per day; 3_restart at 80 mg per day. (b) Patient 2. (c) Patient 3.

Patient 2

A 76-year-old woman with a recent cerebral transient ischemic attack consulted in April 2021 for general deterioration followed by discolored stools. A CT scan and then an endoscopy ultrasound (EUS)-guided biopsy revealed a locally advanced 3-cm cephalic PDAC. A first-line treatment by FOLFIRINOX was initiated in June 2021. After six cycles, CT scan and pancreatic MRI showed RECIST 1.1 PR with no arterial contacts and no distant lesions. The patient underwent pancreaticoduodenectomy in October 2021 with no complications. Pathological analysis showed a pT1cN0R0 well-differentiated PDAC with the following IHC profile (TTF1−, CDX2+, CK7+, CK20−). She then received adjuvant FOLFIRINOX for six additional cycles until March 2022. Isolated CA 19.9 elevation was observed from October 2022, followed by a local recurrence associated with a pulmonary, hepatic, and lymph node metastatic progression on a CT scan in April 2023. An 18F-FDG PET also revealed bone metastasis.

A molecular analysis on the PDAC resected specimen was performed by NGS AmpliSeq for Illumina^® Focus Panel covering 52 genes of interest. The analysis revealed a KRAS WT/EGFR-activating exon 19 deletion: EGFR(NM_005228.5):c.2240_2264delinsCGAAAGA, p.(Leu747_Ala755delinsSerLysAsp) with a VAF of 39%. A pathogenic variant of TP53 was also found: TP53(NM_000546.6):c.772G>T, p.(Glu258Ter) with a VAF of 22%. The EGFR variant was confirmed by a second analysis on the PDAC resected specimen (VAF of 41%) and by a May 2023 liquid biopsy (VAF of 2.1%). Considering the short delay of recurrence, the patient’s frailty (77 years at the relapse), the limited data of gem-based chemotherapy in this situation, and its poor safety profile, targeted therapy was proposed over second-line chemotherapy. After discussion in a molecular multidisciplinary meeting and informed patient agreement, osimertinib (80 mg a day) was started in May 2023.

An 18F-FDG PET at 4 weeks showed pulmonary and lymph node response with hepatic and bone metastases stability (Figure 1(b)). Biological and molecular responses (ctDNA clearance) were also obtained after 2 weeks of treatment (Figure 2(b)). A CT scan in July 2023 showed tumor response (not assessable per RECIST). Due to digestive toxicity (grade 2 diarrhea), a dose reduction was implemented from mid-August to 80 mg/40 mg every other day. Ongoing radiological and biological responses were maintained in October 2024. The patient is still receiving osimertinib with grade 1 diarrhea and grade 1 asthenia.

Patient 3

A 56-year-old woman consulted for epigastric pain and 4-kg weight loss in December 2021. A CT scan revealed a cephalic pancreatic mass with suspect liver nodules. EUS-guided pancreatic biopsy showed a low-differentiated PDAC (IHC: TTF1−, CK7+, CK20−). First-line FOLFIRINOX was started in February 2022 with PR (−20% RECIST) observed at 4 months. In January 2023, after 18 cycles of FOLFIRINOX, a new opioid requiring pain and a CT scan confirmed progression.

A molecular analysis on the first pancreatic biopsy was performed by NGS Custom Solution CGYP panel (Sophia Genetics^®) covering 96 genes of interest. The analysis revealed a KRAS WT/EGFR-activating exon 19 deletion, EGFR(NM_005228.5):c.2240_2257del, p.(Leu747_Pro753delinsSer) (VAF of 10%, cellularity of 50%). A TP53 variant, TP53(NM_000546.4):c.499C>T, p.(Gln167Ter) was associated (VAF of 12%). After discussion in a molecular multidisciplinary meeting and informed patient agreement, osimertinib (80 mg a day) was started in February 2023.

A clinical response was obtained with opioids stopped after 2 months. RECIST 1.1 PR was observed on a June 2023 CT scan. A biological response was also obtained (Figure 2(c)). The patient presented grade 1 diarrhea with no treatment discontinuation or dose reduction needed. In October 2023, radiological and biological progression was observed. Osimertinib was stopped and gemcitabine/nab-paclitaxel started. After two cycles, a new progression was shown on a January 2024 CT scan and the patient died in March 2024.

Discussion

About 90% of PDAC harbor KRAS pathogenic variants.^11,12 In KRAS WT PDAC, the most frequently altered gene is TP53 (44%) followed by BRAF (13%). Mutations, gene fusions, and amplifications are found in PDAC at low frequencies and allelic fractions, reflecting marked intratumor and interindividual heterogeneity and a complex genomic landscape.¹¹

EGFR is supposed to play a role in the pathogenesis of PDAC as it is frequently overexpressed and has been associated with poor prognosis.^22–24 In fact EGFR, RAS, BRAF, and MEK are all members of the MAP kinase pathways which are altered in nearly all PDAC.^11,25 A statistically but not clinically significant 10-day gain in overall survival for the combination erlotinib plus gemcitabine versus gemcitabine had been shown in 2007 in an international randomized phase III study without any molecular selection.²³ A recent Chinese phase III trial showed a non-statistically significant survival benefit for adding nimotuzumab, an anti-EGFR antibody, to gemcitabine in first-line metastatic KRAS WT PDAC without EGFR mutation screening.²⁶ PDAC without KRAS mutation and with EGFR activating variants are notably rare (<1%)^11,12,26,27 and might be the ones benefiting the most from EGFR-targeted therapies.

A systematic review of the literature shows a small number of metastatic PDAC with KRAS WT/EGFR activating mutations treated with targeted therapies,^{13,14,16–18} almost all by erlotinib (alone or with a capecitabine backbone chemotherapy; Table 1). A PR was obtained for 5/7 patients (disease control in 7/7) and PFS ranged from 3 to 12 months. In two cases, progression under erlotinib was documented and explained by a characterized resistance mutation including the well-known T790M.^17,18

Table 1.

Systematic literature review of metastatic PDAC with KRAS wild-type/EGFR activating mutations who received targeted therapy.

N	EGFR mutation	Effect on protein	KRAS status	Age at diagnosis	Sex	Localization	Stratification at diagnosis	Metastatic sites	Metastatic line of targeted treatment	Treatment regimen	Best response	PFS, in months	Resistance mutations	Reference
2	c.2235_2249del	E746_A750del (for both)	NA	NA	NA	NA	Metastatic	NA	Not described	Capecitabine/erlotinib	Stable disease (for both)	>3	NA	Kwak et al., 2006¹³
1	Deletion (not described)	Not described	WT	NA	NA	Body	Metastatic	NA	2	Capecitabine/erlotinib 100 or 150 mg	Partial response	>8	NA	Zill et al., 2015¹⁴
1	Deletion/insertion (not described)	E746_S752delinsV	WT	45	Female	Head	Metastatic	Liver, lungs, bones, lymphatic	4	Furmonertinib 80 mg	Partial response	4.7	NA	Ma et al., 2023¹⁵
1	Deletion/Insertion (not described)	E746_T751delinsVP	WT	58	Female	Head	Metastatic	Liver, peritoneal	3	Erlotinib 150 mg	Partial response	12	NA	Park et al., 2021¹⁶
1	Deletion/Insertion (not described)	L747_P753delinsS T790M	WT	57	Male	Head	Resectable	Liver, local (bed surgery)	4 5	Erlotinib 150 mg Followed by osimertinib 80 mg	Partial response Progressive disease	7.5 2	T790M	Cecchini et al., 2017¹⁷
1	Deletion/insertion (not described)	E746_T751delinsVP A647T	WT	76	Female	NA	Metastatic	Peritoneal	2 4	Erlotinib 75 mg Followed by gemcitabine + paclitaxel by Osimertinib	Partial response Progressive disease	12 3	A647T	Patel et al., 2020¹⁸

A647T involves EGFR exon 17 and not exon 19.

EGFR, epidermal growth factor receptor; KRAS, Kristen rat sarcoma; NA, non-available; PFS, progression-free survival; WT, wild type.

Erlotinib is a first-generation TKI designed to cover EGFR L858R and exon 19 mutations frequently found in NSCLCs. Its clinical benefit was tempered by a systematic genetic resistance arising 10–12 months after initiation, most often a T790M variant. Osimertinib is a third-generation TKI developed to target a broad spectrum of EGFR mutations including T790M. In the pivotal FLAURA trial, osimertinib demonstrated its superiority over erlotinib for naïve metastatic EGFR-mutated NSCLC and was instituted as the new first-line gold standard treatment.²⁸ Nevertheless, under osimertinib also, resistance mechanisms including MET/HER2 amplification and activation of the RAS–MAP kinase or RAS–PI3K pathways ineluctably develop.²⁹ In our literature review, only two patients with PDAC received osimertinib, both after progression under erlotinib, with progressive disease as the best response. However, considering ESMO guidelines for EGFR-altered NSCLC and the emergence of a T790M mutation under erlotinib in our literature review which suggests similar resistance mechanisms to erlotinib for NSCLC and PDAC (Table 1), our multidisciplinary meetings proposed osimertinib as a targeted treatment.

Here we describe three early and prolonged responses to osimertinib in first-, second-, and third-line metastatic PDAC settings. KRAS WT/EGFR exon 19 activating variants were documented for two patients on multiple solid tissue samples and on liquid biopsies at different times. Biological, molecular, metabolic, and radiological responses were obtained in less than 1 month (Figures 1 and 2) and PFS ranged from 6 to >17 months. These results have to be put in parallel with the results reported in Table 1 with erlotinib (PFS: 3–12 months) but also with the 3-month PFS for approved second-line therapy 5-FU/liposomal irinotecan⁴ and the 6.4 and 5.5-month PFS for first-line therapies FOLFIRINOX and gemcitabine/nab-paclitaxel.^2,3 Due to the rarity of these variants in PDAC, no data are available regarding the prognosis of this subgroup independently from targeted therapies. However, these data suggest a meaningful benefit of targeted agents in this setting, which is in line with previous studies showing better outcomes for PDAC when treated with matched therapies.¹⁰

Interestingly, known resistance mechanisms to EGFR-TKIs in lung cancer were detected through ctDNA analyses at progression for patient 1, suggesting similar resistance pathways across different tumor types. Unfortunately, no molecular analysis was performed at progression in patient 3.

Safety was concordant with toxicities known in NSCLC. Digestive toxicity was the main limiting point necessitating treatment discontinuation for patient 1 and dose reduction for patients 1 and 2. Dose reduction for patient 1 was associated with under-therapeutic plasmatic concentrations and biological progression (Figure 2(a)). Therefore, osimertinib plasmatic dosage when dose reduction is proposed could be useful.³⁰

Conclusion

Recent progress in advanced PDAC has relied on targetable molecular alterations, particularly in the KRAS WT subgroup. In this report, osimertinib was associated with clinically significant efficacy in KRAS WT/EGFR exon 19-mutated advanced PDAC and should be considered for these patients. Our observations argue for the in-depth investigation of rare molecular alterations in KRAS WT PDAC. More clinical cases are needed to comfort our observations as prospective validation might never be considered knowing the rarity of these alterations. Similar resistance mechanisms across different tumor types seem to emerge under osimertinib and may one day be targetable.

Supplemental Material

sj-docx-1-tam-10.1177_17588359241312078 – Supplemental material for Prolonged response to osimertinib in three patients with refractory metastatic pancreatic adenocarcinomas with EGFR exon 19 deletion: a case report and literature review

Supplemental material, sj-docx-1-tam-10.1177_17588359241312078 for Prolonged response to osimertinib in three patients with refractory metastatic pancreatic adenocarcinomas with EGFR exon 19 deletion: a case report and literature review by Timothée Vigié, Alexandre Perrier, Brice Chanez, Julien De Martino, Loëtitia Favre, Florence Coulet, Jean-Baptiste Bachet, Erell Guillerm and Léo Mas in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

The authors acknowledge the assistance of Louis de Mestier, MD PhD, in the preparation of the manuscript.

Declarations

ORCID iD

Timothée Vigié

Supplemental material

Supplemental material for this article is available online.

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