Purpose: Programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors have shown efficacy in metastatic esophageal squamous cell carcinoma (ESCC) therapy. However, data is still limited regarding neoadjuvant immunotherapy for operable ESCC. Materials and Methods: Patients with clinical stage T2 or T3 and N0 ESCC received three cycles of nivolumab therapy every two weeks before surgical resection. The primary endpoint is major pathologic responses (MPR) rate (≤ 10% of residual viable tumor [RVT]). Results: Total 20 patients completed the planned nivolumab therapy. Among them, 17 patients underwent surgery as protocol, showing MPR in two patients (MPR rate, 11.8%), including one pathologic complete response, on conventional pathologic response evaluation. Pathologic response was re-evaluated using the immune-related pathologic response criteria based on immune-related RVT (irRVT). Three patients were classified as immunologic major pathologic response (iMPR; ≤ 10% irRVT, iMPR rate: 17.6%), five as pathologic partial response (> 10% and < 90% irRVT), and nine as pathologic nonresponse (≥ 90% irRVT). The combined positive score (CPS) for PD-L1 in the baseline samples was predictable for iMPR, with the probability as 37.5% in CPS ≥ 10 (3/8) and 0% in CPS < 10 (0/9). Conclusion Although the efficacy of neoadjuvant nivolumab therapy was modest in unselected ESCC patients, further researches on neoadjuvant immunotherapy are necessary in patients with PD-L1 expressed ESCC.

Purpose: Alectinib and brigatinib are second-generation anaplastic lymphoma receptor tyrosine kinases (ALKs) that are widely used as first-line therapy for treating ALK-positive advanced non–small cell lung cancer (NSCLC). Given the lack of a head-to-head comparison of these drugs as first-line therapies, this retrospective observational study aimed to compare the real-world efficacy and safety of alectinib and brigatinib. Materials and Methods: Patients who received alectinib or brigatinib as the first-line treatment for ALK-positive advanced NSCLC were evaluated for clinical outcomes of objective response rate (ORR), intracranial ORR, time to next treatment (TTNT), progression-free survival (PFS), overall survival (OS), and safety profiles. Results: Of 208 patients who received either alectinib or brigatinib as a first-line treatment, 176 received alectinib and 32 received brigatinib. At the data cutoff point, the median follow-up duration was 16.5 months (95% confidence interval [CI], 14.7 to 18.3) in the brigatinib group and 27.5 months (95% CI, 24.6 to 30.4) in the alectinib group. The ORR was 92.5% with alectinib and 93.8% for brigatinib. The intracranial ORR rates were 92.7% (38/41) and 100% (10/10), respectively. The rate of PFS at 12 months was comparable between the alectinib group and the brigatinib groups (84.4% vs. 84.1%, p=0.64), and the median TTNT, PFS, and OS were not reached in either group. Treatment-related adverse events were usually mild, and treatment discontinuation due to adverse events was rare (alectinib 4.5% vs. brigatinib 6.25%). Conclusion Alectinib and brigatinib had similar clinical benefits when used as the first-line treatment of NSCLC patients with ALK rearrangement in the real world.

Purpose: Optimal treatment for stage IIIA/N2 non–small cell lung cancer (NSCLC) is controversial. We aimed to assess the efficacy and safety of adjuvant pembrolizumab for stage IIIA/N2 NSCLC completely resected after neoadjuvant concurrent chemoradiation therapy (CCRT). Materials and Methods: In this open-label, single-center, single-arm phase 2 trial, patients with stage IIIA/N2 NSCLC received adjuvant pembrolizumab for up to 2 years after complete resection following neoadjuvant CCRT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. As an exploratory biomarker analysis, we evaluated the proliferative response of blood CD39+PD-1+CD8+ T cells using fold changes in the percentage of proliferating Ki-67+ cells from days 1 to 7 of cycle 1 (Ki-67D7/D1). Results: Between October 2017 and October 2018, 37 patients were enrolled. Twelve (32%) and three (8%) patients harbored EGFR and ALK alterations, respectively. Of 34 patients with programmed cell death ligand 1 assessment, 21 (62%), nine (26%), and four (12%) had a tumor proportion score of < 1%, 1%-50%, and ≥ 50%, respectively. The median follow-up was 71 months. The median DFS was 22.4 months in the overall population, with a 5-year DFS rate of 29%. The OS rate was 86% at 2 years and 76% at 5 years. Patients with tumor recurrence within 6 months had a significantly lower Ki-67D7/D1 among CD39+PD-1+CD8+ T cells than those without (p=0.036). No new safety signals were identified. Conclusion Adjuvant pembrolizumab may offer durable disease control in a subset of stage IIIA/N2 NSCLC patients after neoadjuvant CCRT and surgery.

Background: The cutaneous adverse effects (AEs) of amivantamab, a novel monoclonal bispecific antibody against the epidermal growth factor receptor and mesenchymal-epithelial transcription factor, have not been investigated. Objective: To analyze the type and prevalence of cutaneous AEs in patients with non-small cell lung cancer (NSCLC) treated with amivantamab. Methods: A single-institution retrospective medical record review was conducted on patients with NSCLC who were treated with amivantamab between January 1, 2021, and June 30, 2023. A total of 37 patients receiving amivantamab monotherapy for NSCLC were included in this study. Demographic data (age, sex, body mass index, age at cancer diagnosis, age at amivantamab therapy initiation, and duration of amivantamab use) and the types and severity of cutaneous AEs were evaluated. Results: Cutaneous AEs occurred in 59.5% of the patients. The most common AEs were maculopapular eruptions (37.8%), paronychia (24.3%), pruritus/xerosis (16.2%), acneiform eruptions (13.5%), pustulosis (5.4%), and scalp rashes (5.4%). No Grade 3 cutaneous AE, which led to the discontinuation of amivantamab therapy, was observed. Conclusion Our data describes an extensive review of cutaneous AEs caused by amivantamab. Further research with a larger patient population is necessary to reliably predict and manage cutaneous AEs associated with amivantamab.

Purpose: We aimed to compare the oncological outcomes and toxicities of definitive proton beam therapy (PBT) and photon beam therapy in patients with limited-stage small cell lung cancer (LS-SCLC). Materials and Methods: We retrospectively reviewed 262 patients with newly diagnosed LS-SCLC who underwent definitive PBT (n = 20; proton group) or photon beam therapy (n = 242; photon group) with concurrent chemotherapy between January 2016 and February 2021 and compared overall survival (OS), progression-free survival (PFS), dose-volume parameters, and toxicities between the groups. Results: The median follow-up duration was 24.5 months (range, 3.7 to 78.7). Baseline lung function was significantly worse and clinical target volume (CTV) was larger in the proton group (CTV: 296.6 vs. 215.3 mL; p = 0.080). The mean lung V10 was 37.7% ± 16.8% and 51.6% ± 24.5% in the proton and photon groups, respectively (p = 0.002). Two-year OS and PFS rates were 57.2% and 35.7% in the proton group and 65.3% and 40.8% in the photon group, respectively (p = 0.542 and 0.748, respectively). Grade ≥2 radiation pneumonitis and esophagitis occurred in 5 (25.0%) and 7 (35.0%) PBT-treated patients and 66 (27.3%) and 40 (16.5%) photon beam therapy-treated patients, respectively (p = 0.826 and 0.062, respectively). Conclusion Although the proton group had poorer lung function and a larger CTV than that in the photon group, both groups exhibited comparable treatment outcomes and radiation-related toxicities in LS-SCLC. PBT may be a valuable therapeutic modality in patients with poor pulmonary function or extensive disease burden owing to its lung-sparing ability.

Purpose: Rearranged during transfection (RET) gene rearrangement is a well-known driver event in non–small cell lung cancer (NSCLC). Pralsetinib is a selective inhibitor of RET kinase and has shown efficacy in oncogenic RET-altered tumors. This study evaluated the efficacy and safety of expanded access program (EAP) use of pralsetinib in pretreated, advanced NSCLC patients with RET rearrangement. Materials and Methods: Patients who received pralsetinib as part of the EAP at Samsung Medical Center were evaluated through a retrospective chart review. The primary endpoint was overall response rate (ORR) per the Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1 guidelines. Secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and safety profiles. Results: Between April 2020 and September 2021, 23 of 27 patients were enrolled in the EAP study. Two patients who were not analyzed due to brain metastasis and two patients whose expected survival was within 1 month were excluded from the analysis. After a median follow-up period of 15.6 months (95% confidence interval [CI], 10.0 to 21.2), ORR was 56.5%, the median PFS was 12.1 months (95% CI, 3.3 to 20.9), and the 12-month OS rate was 69.6%. The most frequent treatment-related adverse events (TRAEs) were edema (43.5%) and pneumonitis (39.1%). A total of 8.7% of patients experienced extra-pulmonary tuberculosis. TRAEs with a common grade of three or worse were neutropenia (43.5%) and anemia (34.8%). Dose reduction was required in nine patients (39.1%). Conclusion Pralsetinib presents a clinical benefit when used in patients with RET-rearranged NSCLC, consistent with a pivotal study.

Purpose: Brain metastasis is common in patients with epidermal growth factor receptor (EGFR)–mutant non–small cell lung cancer (NSCLC) at initial presentation. A previous study showed that brain radiotherapy (RT) before first-generation (first-G) EGFR–tyrosine kinase inhibitor (TKI) therapy is associated with longer overall survival than TKI therapy alone. However, there is no data regarding the role of additional brain RT before afatinib therapy. Materials and Methods: Between October 2014 and June 2019, EGFR-mutant NSCLC patients with brain metastases who started first-G EGFR-TKIs (gefitinib or erlotinib) or afatinib as first-line therapy were retrospectively analyzed. This study compared overall survival and intracranial progression-free survival (PFS) between patients who received EGFR-TKIs alone and EGFR-TKIs with brain RT and either a first-G EGFR-TKI or afatinib, respectively. Results: The median follow-up duration was 29.6 months (range, 1.5 to 116.9 months). In the first-G EGFR-TKI group (n=155), 94 patients (60.6%) received the first-G EGFR-TKI alone and 61 patients (39.4%) received brain RT prior to their first-G EGFR-TKI. In the afatinib group (n=204), 126 patients (61.8%) received afatinib alone and 78 patients (38.2%) received brain RT prior to afatinib. There was no difference in overall survival rates between the groups with RT (35.6 months: 95% confidence interval [CI], 27.9 to 43.3) and without RT (31.4 months: 95% CI, 23.9 to 38.9) in the afatinib group (p=0.58), but there was a significant difference in overall survival in the first-G EGFR-TKI group in a manner favoring additional brain RT (41.1 months: 95% CI, 30.5 to 51.7 vs. 25.8 months: 95% CI, 20.1 to 31.5; p=0.02). Meanwhile, median intracranial PFS was not different between patients who received EGFR-TKI therapy alone vs. EGFR-TKI therapy with brain RT in both the first-G EGFR-TKI (p=0.39) and afatinib (p=0.24) groups. Conclusion Afatinib therapy alone showed comparable survival outcomes to those of afatinib with brain RT. The current study suggests that brain RT could be an optional, not mandatory, treatment modality when afatinib therapy is considered in patients with EGFR-mutant NSCLC.

Purpose: The impact of epidermal growth factor receptor (EGFR) mutation in locally advanced non–small cell lung cancer (NSCLC) remains controversial. This study was conducted to investigate the clinical outcomes and recurrence patterns after definitive chemoradiotherapy (CRT) in patients with unresectable stage III non-squamous-cell lung cancer according to EGFR mutation status. Materials and Methods: We retrospectively reviewed 604 patients with pathologically confirmed stage III NSCLC who were treated with definitive CRT and were examined for EGFR mutation at Samsung Medical Center, Korea, from January 2013 to December 2018. Among them, we identified 236 patients with stage III non-squamous-cell lung cancer who were treated with definitive CRT and were examined for EGFR mutation status. We analyzed the frequency of EGFR mutation, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and recurrence pattern. Results: Among 236 patients, EGFR mutation was detected in 71 patients (30.1%) and the median follow-up duration was 41.7 months. There were no significant differences in PFS (9.9 vs. 10.9 months, p=0.236), and ORR to CRT (93.0% vs. 90.3%, p=0.623) according to EGFR mutation status. However, the EGFR mutant group showed significantly higher recurrence (88.7% vs. 75.2%, p=0.022), distant metastasis (76.1% vs. 61.2%, p=0.036) rates, especially brain (38.0% vs. 12.7%, p < 0.001), and better median OS (59.2 vs. 41.3 months, p=0.037) compared with patients without EGFR mutation. Conclusion Patients with EGFR mutation–positive unresectable stage III non-squamous lung cancer exhibited higher recurrence and distant metastasis rates, especially brain metastasis.

Purpose: Metachronous brain-only oligorecurrence in patients with non–small cell lung cancer (NSCLC) is a rare event with favorable prognosis, but the clinical outcome has not been fully determined. We retrospectively analyzed clinical outcomes and prognostic factors in metachronous brain-only oligorecurrence in patients with NSCLC who underwent definitive treatment. Materials and Methods: We reviewed 4,437 NSCLC patients without oncogenic driver mutations who underwent definitive treatment between 2008 and 2018. Among them, we identified 327 patients who developed 1 to 5 brain metastases with or without systemic metastasis. Of the 327 patients, 71 had metachronous brain-only oligorecurrence without extracranial progression and were treated with local therapy to the brain. Overall survival (OS), progression-free survival (PFS), and prognostic factors affecting OS were analyzed. Results: The median OS was 38.9 months (95% confidence interval [CI], 21.8 to 56.1 months) in 71 patients. The 2-year OS rate was 67.8% and the 5-year OS rate was 33.1%. The median PFS was 25.5 months (95% CI, 12.2 to 14.4 months). The longest surviving patient had a survival period of 115 months. Through multivariate analysis, Eastern Cooperative Oncology Group ≥ 1 (hazard ratio, 5.33; p=0.005) was associated with poor survival. There was no significant difference in OS between patients with local therapy and those with local plus systemic therapy (18.5 months vs. 34.7 months, p=0.815). Conclusion Metachronous brain-only oligorecurrence NSCLC patients who underwent definitive treatment experienced long-term survival with local therapy, highlighting the unique patient population. The role of systemic chemotherapy in this patient population requires further investigation.

Clinical trials have not consistently supported the use of induction chemotherapy (IC) for locally advanced head and neck squamous cell cancer. Hypopharynx and base of tongue (BOT) cancer has shown relatively poor survival. We investigated the role of IC in improving outcome over current chemoradiotherapy (CRT) in patients with hypopharynx and BOT cancer. Methods: Treatment-naïve patients with stage III/IV (M0) hypopharynx or BOT cancer were randomly assigned to receive CRT alone (CRT arm: cisplatin 100 mg/m2 on D1 3-weekly, two times plus radiotherapy 68.4 Gy/30 fractions on weekdays) versus two 21-day cycles of IC with TPF (docetaxel & cisplatin 75 mg/m2 on D1, and fluorouracil 75 mg/m2 on D1-4) followed by the same CRT regimen (IC arm). The primary endpoint was progression-free survival (PFS). Results: This study closed early after enrollment of 36 patients (19 in the CRT arm, 17 in the IC arm). After a median follow-up of 47.2 months, there was no significant difference in PFS: the median PFS was 26.8 months for the CRT arm and was not reached for the IC arm (p = 0.13). However, the survival curves were widely separated with a plateau after 3 years, suggesting a potential survival benefit from IC: 3-year PFS rates were 45% and 68%, and 3-year overall survival rates were 56% and 86%, in the CRT and IC arms, respectively. Conclusions: This study failed to demonstrate that induction TPF chemotherapy improves survival in patients with BOT and hypopharynx cancer. However, it suggested a favorable outcome with IC to this population.