Durable Response of Pembrolizumab for EGFR Mutation-positive Lung Adenocarcinoma with Early Progression to Osimertinib in First-line Treatment

Abstract

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is the standard first-line treatment for EGFR mutation-positive non-small-cell lung cancer (NSCLC) and demonstrates favorable disease control. Conversely, immune checkpoint inhibitors (ICIs) that target programmed cell death-1/programmed cell death ligands demonstrate a restrictive tumor response. We herein report a patient who achieved a durable response to pembrolizumab following early progression within two months of osimertinib administration for EGFR mutation-positive lung adenocarcinoma. Our findings suggest that treatment with ICIs for patients with EGFR mutation-positive NSCLC experiencing early progression to osimertinib as first-line treatment might represent a viable approach.

Introduction

Epidermal growth factor receptor (EGFR) mutations are key drivers of mutations in non-small-cell lung cancer (NSCLC) and serve as predictive markers for response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). In the FLAURA trial, osimertinib, a third-generation EGFR-TKI, significantly prolonged the progression-free survival (PFS) (median PFS of approximately 19 months) compared to first-generation EGFR-TKIs (gefitinib and erlotinib) and is the standard of care in the first-line treatment of these populations, as recommended by several guidelines (1-5).

Despite favorable disease control, most patients eventually experience disease progression. Following disease progression under osimertinib treatment, platinum-based chemotherapy typically remains the current standard of care as second-line treatment (6). However, there is a need for further development of treatment options for EGFR mutation-positive lung cancers following osimertinib resistance.

Immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death ligand 1 (PD1/PD-L1) pathway have demonstrated survival benefits in patients with NSCLC and are widely used in clinical practice (7). However, the antitumor activity of ICIs against EGFR mutation-positive NSCLC has been modest compared to that of EGFR wild-type NSCLC in several previous studies (8,9).

We herein report a patient who had a durable response to the ICI pembrolizumab for EGFR mutation-positive lung adenocarcinoma with early progression to osimertinib treatment.

Case Report

A 71-year-old woman with no history of smoking underwent right lower lobectomy and mediastinal lymph node dissection and was diagnosed with pathological T2aN0M0 stage IB lung adenocarcinoma (Figure). The patient had hypertension, dyslipidemia, and cataracts. Approximately one year later, computed tomography (CT) revealed enlargement of the right hilar and multiple mediastinal lymph nodes, and endobronchial ultrasound-guided transbronchial needle aspiration of the mediastinal lymph node confirmed adenocarcinoma. Both the primary lung tumor and recurrent mediastinal lymph node exhibited exon21 L858R mutation by cobas^Ⓡ EGFR Mutation Test v2 and PD-L1 tumor proportion score of ≥50% (evaluated using PD-L1 IHC 22C3 pharmDx KIT). The patient was diagnosed with postoperative local recurrence, and treatment with osimertinib (80 mg/day) was initiated owing to reluctance to undergo radiotherapy because of concerns about adverse events.

Figure.

Clinical course. Chest computed tomography shows enlargement of multiple mediastinal lymph nodes at postoperative recurrence. After administration of osimertinib, the #2R (white arrows) and #7 (yellow arrows) lymph nodes increased in size from 15 mm to 18 mm. Following progression with osimertinib, immediate treatment with pembrolizumab led to a reduction in the size of multiple mediastinal lymph nodes. PFS: progression-free survival, CR: complete response, PD: progression disease

Eight weeks after osimertinib initiation, significant enlargement of the right hilar and multiple mediastinal lymph nodes was observed, indicating disease progression. Considering the patient's Performance Status of 1 and her refusal of cytotoxic chemotherapy, the patient received pembrolizumab at a dose of 200 mg every 3 weeks. After two cycles of treatment, CT showed remarkable shrinkage of the mediastinal lymph nodes, and a complete response (CR) was achieved. However, pembrolizumab was discontinued after only two cycles because of the development of a severe skin rash (grade 3). Following treatment discontinuation, the skin disorder improved, and pembrolizumab was not resumed in accordance with the patient's preference.

Eight months after the initiation of osimertinib treatment, the patient showed no recurrence and maintained a CR.

Discussion

We herein report a patient with EGFR mutation-positive lung adenocarcinoma who had early progression to osimertinib but had a durable response to pembrolizumab.

In the FLAURA trial, osimertinib demonstrated significant antitumor activity against EGFR mutation-positive NSCLC compared to first-generation EGFR-TKIs, with a reported median PFS of approximately 19 months (5). However, initial resistance to osimertinib affects approximately 20-30% of patients and is associated with pre-existing molecular alterations, including heterogeneity in EGFR mutations and the presence of co-dominant genetic alterations, prior to molecular-targeted therapy (10). Clarifying the clinical and molecular characteristics of these patients is essential for the personalized treatment of lung cancer with EGFR mutations.

Recently, several retrospective studies have indicated that high PD-L1 expression is associated with a reduced PFS in advanced EGFR mutation-positive NSCLC patients treated with osimertinib as first-line therapy (11,12). Zhang et al. demonstrated that PD-L1 expression may contribute to primary resistance to EGFR-TKIs by mediating epithelial-mesenchymal transition through activation of the TGF-β/Smad canonical signaling pathway in EGFR mutation-positive NSCLC cell lines (13). In this case with high PD-L1 expression (≥50%), early disease progression occurred after only 2 months of osimertinib treatment, consistent with previous reports (11,12).

Monotherapy with anti-PD-1/PD-L1 antibodies for EGFR mutation-positive NSCLC has shown limited antitumor efficacy, with previously reported objective response rates (ORRs) of 4-19% and a median PFS of 1.7-1.9 months (8,9). In addition, even in patients with EGFR mutation-positive NSCLC exhibiting high PD-L1 expression (over 50%), the ORR for PD-1/PD-L1 antibody monotherapy was only 16.67%, and the median PFS was just 2.79 months, indicating modest efficacy of immunotherapy in these populations (14). Consequently, considering the low efficacy of immunotherapy for EGFR mutation-positive NSCLC, including cases with high PD-L1 expression, platinum-based chemotherapy is generally preferred as subsequent therapy after progression to osimertinib. Despite early disease progression after osimertinib treatment, pembrolizumab monotherapy led to a drastic response. Several retrospective studies have reported that a short PFS (≤10 months) associated with EGFR-TKIs correlates with a better response to ICI therapy in patients with EGFR-TKI-resistant NSCLC (15,16). However, these studies did not include cases of first-line osimertinib treatment; therefore, the relationship between the PFS with first-line osimertinib and the therapeutic effects of ICIs remains unclear.

A high tumor mutation burden (TMB) has been reported to be associated with a shortened time to treatment discontinuation in patients with EGFR mutation-positive lung cancer treated with EGFR-TKIs (17). As mentioned above, high PD-L1 expression (PD-L1 ≥50%) has also been associated with a shortened PFS in osimertinib treatment as a first-line therapy for patients with advanced EGFR mutation-positive NSCLC (12). High TMB and PD-L1 expression are predictive factors for the response to monotherapy with anti-PD-1 antibodies (7,18). Based on these findings, a short PFS with osimertinib in the first-line setting might indicate a high TMB and PD-L1 expression, which could have resulted in a durable response to pembrolizumab in this case, although the TMB was not measured. The short PFS with osimertinib treatment in the first-line setting for EGFR mutation-positive NSCLC may serve as an indicator of the response to anti-PD1/PD-L1 antibodies after disease progression to this treatment.

Conclusion

We herein report a patient with EGFR mutation-positive adenocarcinoma who showed a durable response to pembrolizumab following early progression to osimertinib as the first-line treatment. Early progression to osimertinib as the first-line treatment for EGFR mutation-positive NSCLC might confer clinical benefits from immunotherapy after disease progression.

The authors state that they have no Conflict of Interest (COI).