ALK Mutations Research Articles

Association between PD-L1 expression with EGFR, ALK, and ROS1 driver oncogene mutations in non-small cell lung cancer.

Driver mutations and immunological expressions have gained importance in recent years for targeted therapies and immunotherapies of nonsmall cell lung cancer (NSCLC). This study examined the association between PD-L1 expression and ALK, ROS1, and EGFR driver oncogene mutations in patients with NSCLC. A total of 501 NSCLC patients were included for analysis. Immunohistochemistry was performed with a PD-L1 clone 22c3. EGFR mutations were detected by PCR. ALK and ROS1 rearrangement analysis was performed with FISH. Results: There was a highly statistically significant difference between PD-L1 expression and EGFR mutation. PD-L1 expression was higher in the EGFR wild-type than in mutated EGFR (P = 0.0002). There was no relationship between PD-L1 expression and ALK and ROS1 mutations (P = 0.8899, P = 0.2512, respectively). PD-L1 expression was higher in nonadenocarcinomas (non-AC) than in adenocarcinomas (AC) (P = 0.0438). The ALK rearrangement and EGFR mutations were higher in ACs (P = 0.0073, P = 0.0012, respectively). ALK, ROS1 rearrangements, and EGFR mutations were higher in nonsmokers (P < 0.05). EGFR mutations were detected more frequently in females than males (P = 0.001). There was no relationship between gender and ALK, ROS1, and PD-L1 (P > 0.05). The prevalence of EGFR, ALK, and ROS1 driver mutations in the Turkish population was 9.3%, 5.3%, and 2.4%, respectively. In conclusion, PD-L1 expression and mutated EGFR status have a highly negative association. PD-L1 expression was higher in EGFR wild-type patients. Therefore, it shows that the opportunity to receive PD-L1-related treatment may be higher in these patients. We think that PD-L1 immunohistochemical evaluation will increase the clinical predictive importance in EGFR wild-type cases.

Lorlatinib vs crizotinib in treatment-naïve patients with advanced ALK+ non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study.

LBA8503 Background: Lorlatinib, a brain-penetrant, 3rd-generation ALK tyrosine kinase inhibitor, demonstrated improved progression-free survival (PFS) and intracranial (IC) activity vs crizotinib in the phase 3 CROWN study in treatment-naïve patients (pts) with advanced ALK+ non-small cell lung cancer (NSCLC). We report long-term efficacy and safety outcomes from the CROWN study after 5 years of follow-up. Methods: 296 treatment-naïve pts with advanced ALK+ NSCLC were randomized 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). In this post hoc analysis, we present investigator-assessed efficacy outcomes, safety, and biomarker analyses. Formal statistical testing was not performed. Results: As of October 31, 2023, 74 of 149 pts (50%) vs 7 of 142 pts (5%) were still receiving lorlatinib vs crizotinib. With a median duration of follow-up for PFS (95% CI) of 60.2 months (57.4-61.6) in the lorlatinib and 55.1 months (36.8-62.5) in the crizotinib arm, median PFS (95% CI) was not reached (NR; 64.3-NR) with lorlatinib and 9.1 months (7.4-10.9) with crizotinib (HR, 0.19; 95% CI, 0.13-0.27). 5-year PFS (95% CI) was 60% (51-68) with lorlatinib and 8% (3-14) with crizotinib. Median time to IC progression (95% CI) was NR (NR-NR) with lorlatinib and 16.4 months (12.7-21.9) with crizotinib (HR, 0.06; 95% CI, 0.03-0.12). In pts without baseline brain metastases in the lorlatinib arm, only 4 of 114 developed brain progression, occurring within the first 16 months of treatment. Efficacy outcomes by baseline brain metastases are shown in the Table. Grade 3/4 adverse events (AEs) occurred in 77% of pts with lorlatinib and in 57% of pts with crizotinib. Treatment-related AEs led to treatment discontinuation in 5% and 6% of pts in the lorlatinib and crizotinib arms, respectively. Safety profile was consistent with that observed in prior analyses. Emerging new ALK mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment (n = 31). Conclusions: After 5 years of follow up, the median PFS in the lorlatinib arm has yet to be reached, corresponding to the longest PFS ever reported in advanced NSCLC. Coupled with prolonged IC efficacy and absence of new safety signals, these results indicate an unprecedented improvement in outcomes for pts with advanced ALK+ NSCLC. Clinical trial information: NCT03052608 . [Table: see text]

Afatinib in patients (pts) with solid tumors with neuregulin 1 (NRG1) fusions: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

3131 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a small cohort of pts with advanced solid tumors with NRG1 fusions treated with afatinib are reported. Methods: Eligible pts had measurable, advanced disease, NRG1fusion, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Pts with non-small cell lung cancer (NSCLC) were eligible if they had no pathogenic mutations in ALK, BRAF, EGFR or ROS1. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 40 mg of afatinib daily until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response, duration of SD, and safety. This cohort was closed after 2 years before completing stage 1 enrollment (n = 10) of the Simon’s 2-stage design used in TAPUR according to a prespecified cohort closure rule. Results: 4 pts with 3 tumor types with NRG1 fusion were enrolled between February 2020 and July 2021. 1 pt had NSCLC with a CD74- NRG1 fusion and achieved a PR that lasted 24 weeks (wks). This pt was a 58-year-old White, non-Hispanic female with ECOG PS 0, 2 prior systemic therapies and progressed after 32 wks on study tx. Co-alterations included CCNE1 amplification (amp), GATA amp, TP53 R65fs*58, and an ALK G1121D variant of unknown significance. 2 pts achieved SD16+: 1 was a 47-year-old White, Hispanic female with colorectal cancer (CRC) with a MATN2- NRG1 fusion, ECOG PS 1, 3 prior systemic therapies and co-alterations in APC, DDX11, FBXW7, FGFR1 and TP53; the other pt was a 49-year-old Black, non-Hispanic male with pancreatic cancer with a NRG1 exon 2 fusion, ECOG PS 1, 5 prior systemic therapies, a comutation in ARID1A. The durations of SD for these 2 pts were 136 and 64 wks, respectively. The pt with CRC underwent resection of a remaining target lesion and is still alive off study drug at 198 wks after the baseline visit as of Dec 2023. 1 pt was a 70-year-old White, non-Hispanic female with CRC with a CD74- NRG1 fusion, ECOG PS 0, 1 prior systemic therapy, and a best response of progressive disease. This pt had comutations in ARID1A, PBRM1 and TP53and progressed at 8 wks. Median OS was 81 wks. No grade 3-5 tx-related adverse events (AE) or serious AEs were reported. Conclusions: Though a small sample size, afatinib demonstrated promising activity in pts with advanced solid tumors with NRG1 fusion, including very durable DC. Additional study in a larger group of pts is warranted to confirm the efficacy of afatinib in pts with NRG1 fusion. Clinical trial information: NCT02693535 .

Treating lung cancer in resource limited setting: Retrospective study from Armenia.

e20055 Background: Lung cancer (LC) is second most common cancer by incidence in Armenia. Every year approximately 800-900 new cases are diagnosed, from all cases 55.5% are in the 4th stage. Methods: We have collected data from three oncology centers in Armenia: Yeolyan Hematology and Oncology Center, Mikaelyan Institute of Surgery, and Muratsan Hospital Complex of Yerevan State Medical University. In this retrospective hospital-based study the data of patients with LC who were treated at these three centers during the 01 Oct 2009 - 31 Dec 2023 period was collected․ Results: Four hundred and eighty-nine LC patients were involved in the final analysis. Male to female ratio was 6:1. From the all patients 10.6% were diagnosed at age ≤ 50, 79,6% of patients 50-70, and 9.6% ≥ 70 years. In 71.6% of all cases, LC was diagnosed in current or former smokers. Only 3% of patients were diagnosed in stage I, 9.8% in stage II, 44.8% in stage III, 41.1% in stage IV, and for 1.2% of patients' stage was unknown. From all cases 74% of patients had non small cell lung cancer (NSCLC), 22.7% small cell lung cancer (SCLC) and 3.3% had other histological types of lung cancer. Of all patients 63% are dead. The median overall survival (mOS) for all stages was 21 months for the entire cohort. Median OS was not reached for stage I ( &gt; 100 months), was 61 months for stage II, 23 months for stage III, and 13 months for stage IV (p &lt; 0,001). ALK mutation was checked in 22.7%, EGFR in 22%,ROS in 14.1%, KRAS in 11.2%, BRAF in 9.8% and of all patients. From all checked AKL was positive in 1.8%, EGFR in 19.4%, ROS in 2.8%, KRAS in 21.8%, BRAF in 8,3% and of cases. For patients with stage IV lung cancer (41.1%), we found a significant difference in mOS in those who received first line immunotherapy in combination with chemotherapy (19,4%) compared to those who received only chemotherapy (74.1%) (mOS: 24 months vs 11 months accordingly, p = 0.014). For stage I-III LC patients, those who received systematic therapy with cisplatin showed better overall survival than those who received systemic therapy with carboplatin (mOS 31 vs 25 months, p = 0.01), but for stage IV LC patients survival difference was not found (mOS 15 vs 12 months, p = 0.24). Conclusions: In Armenia, lung cancer is mostly diagnosed in the advanced stage where overall survival is approximately one year. In our study population, those who received immunotherapy in combination with chemotherapy showed doubled mOS, compared with only chemotherapy. In the nonmetastatic group, chemotherapy with cisplatin showed a significant increase in mOS compared with carboplatin.

Clinical application of individualized tumor-informed circulating tumor DNA for therapeutic response and relapse prediction in patients with neuroblastoma.

10053 Background: Patients with high-risk neuroblastoma (NB) generally present with widely metastatic disease and often relapse despite intensive therapy. At present, circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) has been studied in various tumors and proven to be valuable in guiding treatment and predicting recurrence, but its application in NB has rarely been reported. This study aimed to assess the effectiveness of tumor-informed ctDNA monitoring for evaluating the response to induction therapy in NB patients, as well as its role in predicting the risk of relapse. Methods: We conducted a prospective cohort study of NB patients. Primary tumor samples were collected at baseline and blood samples were collected sequentially from baseline until disease progression or the last follow-up. Tumor tissue samples were subjected to whole exome sequencing (WES), and clonal mutations were selected for the individualized MRD panel. Sequencing was conducted at OrigiMed, a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Results: Our cohort included 43 individuals diagnosed with NB, with a median age of 3.5 years (0.42-40 years). WES revealed that 75% (2054/2753) of the mutated genes were unique to each patient, and 98.9% (704/712) of the selected tumor-informed single nucleotide variants were variants of unknown significance, suggesting that individualized tumor-informed MRD (n = 23) is superior to fixed tumor-agnostic panel (n = 20) MRD in NB. A successful individualized MRD panel was constructed for 53.5% (23/43) of patients, with a remarkable 92.3% success rate for those older than 5 years (p &lt; 0.01). The initial positivity rate for ctDNA detection was 68%, with the initial positivity rate being associated with the stage (p &lt; 0.01). During treatment and follow-up, 0/6 of the patients whose ctDNA levels remained negative experienced a relapse, whereas 2/5 patients who had a negative conversion or an increase in positivity experienced a relapse. In addition, ctDNA changes matched radiological evaluations in 94% of patients. Notably, ctDNA was detected prior to radiological relapse, with a lead time of 6 months in one patient. Patients can be divided into four groups according to the mutation landscape: ALK mutation, MYCN amplification, chromosome amplification, and other groups. Among them, the rate of ctDNA clearance was the highest in the chromosome amplification group, indicating that patients in this group were the most sensitive to chemotherapy. Conclusions: Individualized tumor-informed ctDNA monitoring shows promise for evaluating therapeutic response and forecasting relapse in NB patients. This approach proves more effective than fixed tumor-agnostic panel-based MRD due to high genetic mutation uniqueness. Clinical trial information: NCT05076071 .

Biomarker testing and targeted therapy use among patients with non-small cell lung cancer in the United States: An analysis using a physician notes real-world database.

11175 Background: Biomarker testing informs treatment decisions by identifying patients who would clinically benefit from targeted regimens, leading to improved patient outcomes. However, the use of guideline-recommended biomarker testing in patients with advanced non-small cell lung cancer (NSCLC) is inconsistent. This study investigates the rates of biomarker testing in patients with NSCLC using a qualitative, real-world database. Methods: Natural language processing (NLP) was used to search and analyze the Amplity Insights database, consisting of transcribed, de-identified, records of physician-patient interactions obtained from patient medical records across the United States. This was a retrospective analysis of patients with a diagnosis of NSCLC (October 2003 - November 2023). Patient characteristics, biomarker testing, and treatment use were summarized and described. Results: 61,018 patients with NSCLC (mean [standard deviation] age of 69.8 [10.5] years) were identified. Among these, 50.6% were female and 87.9% identified as white. Among records with staging information, 26.6% had early-stage disease (stage 0-II) and 73.4% had late stage (stage III-IV) disease. In total, 13.4% (n=8,151) of all patients received biomarker testing. 13.3% (n=879) and 22.4% (n=2,402) of patients with stage III and IV, respectively, had biomarker testing performed; rates were higher in patients who were receiving care from an oncologist (16.8%, 31.0%, respectively). Among patients who had a confirmed actionable mutation (n=6,387), 35.9% received an appropriately matched targeted therapy and 10.1% received a nonindicated targeted therapy without harboring the indicated mutation. Of these, 40.7%, 22.7%, and 37.7% of patients harbored EGFR or ALK mutations, or were PD-L1 positive, respectively, and 35.8%, 17.8%, and 40.2% received the appropriate indicated treatment, respectively, based on testing. ALK-, EGFR-, and PD-L1-targeted therapies were taken by 12.1%, 9.4%, and 1.9% of patients, respectively, without evidence of the indicated biomarkers. Conclusions: These findings suggest that biomarker testing may be underutilized and that many patients may not be benefitting from treatment with precision therapies, highlighting the need for additional educational strategies to optimize precision oncology and elevate patient outcomes.

Amivantamab plus capmatinib in advanced non-small cell lung cancer (NSCLC) harboring MET alterations: Recommended phase 2 combination dose and preliminary dose-escalation results from the phase 1/2 METalmark study.

8619 Background: Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell-directing activity. Ami monotherapy has demonstrated meaningful clinical activity in MET-driven advanced NSCLC, including in patients (pts) harboring MET exon 14 skipping mutations (METex14) (1) and MET amplification (amp) (2) Capmatinib (cap) is an intracellular-targeting MET TKI approved for METex14-mutated advanced NSCLC (3). Simultaneously targeting MET’s extracellular and intracellular regions could achieve more potent inhibition than either agent alone. Here, we report preliminary results and the identification of the recommended phase 2 combination dose (RP2CD). Methods: The open-label METalmark study (NCT05488314) includes a combination dose selection phase in pts with advanced NSCLC, followed by an expansion phase in pts with treatment-naïve METex14, refractory METex14, or MET amp (3 cohorts), lacking EGFR or ALK mutations. For phase 1 dose-selection, pts must have had disease progression on or intolerance to prior therapy. Dose levels assessed were DL0 at 700 mg (1050 mg if ≥80 kg) ami IV + 400 mg oral cap twice daily (BID) and DL+1 at 1050 mg (1400 mg if ≥80 kg) ami IV + 400 mg cap oral BID. Primary endpoints were dose-limiting toxicity (DLT) during Cycle 1, Days 1-28 and safety. Results: As of 8 Nov 2023, 18 pts were dosed, with a median follow-up of 3.3 months. There were 10 pts at DL0 (9 DLT evaluable) and 8 pts at DL+1 (all DLT evaluable). In the first DL0 cohort, 1 pt (of 4 DLT evaluable) reported a DLT, grade 3 nausea, prior to the adoption of nausea/vomiting recommendations. Among the remaining 5 DLT-evaluable pts at DL0, there were no DLTs, meeting prespecified criteria for escalation to DL+1. No DLTs were observed among the 8 pts at DL+1. Among all pts, the median number of prior lines was 3 (range, 1–5) and the following driver mutations were detected: EGFR Ex19del (6 pts) and L858R (6 pts), METex14 (4 pts), MET amp (2 pts), EGFR Exon 20 insertion (1 pt), and KRAS G12V (1 pt). There was 1 partial response (PR; MET amp+Ex19del), 2 unconfirmed PRs (1 METex14, 1 L858R; both ongoing), and 8 stable diseases observed as a best overall response. Preliminary PK data suggest similar exposure for the combination vs individual agents. Among the 8 treatment discontinuations, 6 were due to progressive disease, 1 withdrew consent, and 1 due to respiratory failure (unrelated to study treatments). Most common AEs were primarily EGFR- and MET-related. Rate of peripheral edema was 28% (5/18), none grade ≥3. Updated results will be reported at the meeting. Conclusions: RP2CD for ami+cap was identified as a combination of each approved dose. Initial safety profile of ami+cap does not appear to have additive MET-related toxicities. 1. Leighl JTO 2023;18(11):S93-94, OA21.04. 2. Haura JCO 2019;37:15_suppl, 9009. 3, Wolf NEJM 2020;383(10):944-957. Clinical trial information: NCT05488314 .

Impact of the tumor proportion score (TPS) and the combined positive score (CPS) on the use of immunotherapy in patients with metastatic non-small cell lung cancer.

e14611 Background: Expression of programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) has often been measured by the Tumor Proportion Score (TPS) (1). Recently, the Combined Positive Score (CPS), which evaluates PD-L1 expression in tumor and inflammatory cells and applies to other types of cancer including gastric and head and neck cancers, was found to be equally predictive of the response to immunotherapy in NSCLC (1). In this study, we aimed to conduct a single center retrospective analysis to evaluate the clinical use and impact of using TPS and CPS data in patients with metastatic NSCLC. Methods: Patients with NSCLC who had TPS and CPS scores and received PD-1/PD-L1 inhibitors between 2021-2022 as a monotherapy or in combination with chemotherapy were included. Patients’ data was retrieved from the electronic medical record data and analysis included histopathological data, lung cancer surgical history, presence of EGFR mutation, ALK mutation, Ki67, use of adjuvant chemotherapy, type of immunotherapy used, and development of immune checkpoint inhibitor- related toxicity and treatment as applicable. TPS and CPS positivity was defined as &gt;1 % and &gt;1 respectively. Statistical methods employed included descriptive approaches such as calculated means as well as the Kaplan-Meier estimate. Results: 40 patients with NSCLC were included. Patients’ age ranged from 19 to 82 years old with an average age of 64.3 years old. Most patients had adenocarcinoma (65 %) and were at stage IV (72.5 %). TPS positivity was identified in 29 patients (72.5 %) and CPS positivity was identified in 35 patients (87.5 %). Patients received immunotherapy mostly as first or second line of treatment (90 %). Immune checkpoint inhibitors received by patients were pembrolizumab (50 %), nivolumab (35 %), atezolizumab (12.5 %), and durvalumab (2.5 %). The median overall survival was 16, 12, and 17 months in the &lt;1 %, 1-49 % and &gt; 49 % TPS groups respectively (p= 0.354); while the median overall survival was 11, 16 and 17 months in the &lt;1, 1-49, and &gt; 49 CPS groups respectively (p= 0.417). It is critical to highlight that there were 7 patients (17.5 %) with TPS of zero who had CPS positivity (score range: 1-10). Most of these patients had adenocarcinoma (71.4 %), received pembrolizumab or atezolizumab (85.7 %) and had a median survival of 16 months. Conclusions: The Combined Positive Score (CPS) has proven to be an effective method in evaluating the level of expression of PD-L1 in NSCLC (1,2). Similar to TPS, CPS provides critical information that can be applied to guide the use of immunotherapy, and which can greatly impact patients with NSCLC. 1. De Marchi et al., 2021. 2. Ulas et al., 2023.

Comprehensive germline and somatic DDR genomic profiles of Chinese patients with multiple primary lung cancer.

e20019 Background: The number of multiple primary lung cancer (MPLC) patients has rapidly increased in recent years. Disruption of the DNA damage repair (DDR) gene is related to cancer risk, progression, and treatment selection. However, the characteristics and significance of DDR alterations remain undefined in MPLC. Methods: A total of 133 Chinese MPLC patients with 308 lesions were enrolled and 784 single-focus lung cancer (SFLC) patients were analyzed as a control in the present study. Genetic testing was performed by utilizing the next-generation sequencing (NGS) of 808 cancer-related genes including 276 DDR genes. The patients were divided into 3 groups: DDR-germline (germline variants, N = 11), DDR-somatic group (somatic variants, N = 98), and the non-DDR group (no DDR variants, N = 24). Results: The overall DDR variants were identified in 82.0% (109/133) of the patients, and a total of 283 variants were found, with almost all being somatic (254/283). The most commonly germline alterations were found in RAD50 (1.5%), WRN (1.5%) and BRCA2 (0.8%), while in the somatic mutations, TP53 (26.3%) showed the highest frequency. DDR-somatic group was more likely to have alterations in TP53, LRP1B, ERBB2 and MYC compared with DDR-germline group. Taken non-DDR group as reference, mutations in TP53 (P&lt;0.05), ALK and PIK3CA were more common in DDR-germline group, but EGFR, RBM10, TP53, LRP1B, TERT and MYC (all P&lt;0.05) in DDR-somatic group. Furthermore, the DDR-somatic group exhibits the highest median tumor mutational burden (6.56) compared with 3.55 (P&lt;0.01) in DDR-germline and 3.69 (P&lt;0.01) in non-DDR group. In addition, the copy number variation (CNV) was statistically different among the three groups (P&lt;0.001). The proportion of copy number gain patients in DDR-somatic group is the highest (28.3%) compared with 12.0% in DDR-germline group and 10.9% in non-DDR group (P&lt;0.01). DDR-somatic MPLC and SFLC patients possessed distinct somatic genomic characteristics, especially with significantly different prevalence in TP53, RBM10, KRAS, BRAF, and ALK (all P&lt;0.05). Moreover, we also found notable differences in the prevalence of TP53 and CNV (both P&lt;0.05) between DDR-germline MPLC and SFLC patients. Conclusions: MPLC patients exhibit a distinctive DDR mutations landscape. The differences in the mutation profile between the DDR-germline and DDR-somatic groups and the distinct actionable genes may indicate the different target-therapy choices for MPLC patients.

Neoadjuvant camrelizumab combined with chemotherapy for resectable stage IIIA-IIIb non-small cell lung cancer: Single arm phase II study.

e20074 Background: This study aimed to evaluate the safety and efficacy of neoadjuvant camrelizumab combined with chemotherapy in patients with resectable non-small cell lung cancer (NSCLC). Methods: In this single-arm phase II clinical trial, patients aged 18-75 with pathologically confirmed resectable stage IIIA-IIIB (T3-4N2) NSCLC without EGFR, ALK, and ROS1 gene mutations were enrolled since December 2022. Patients were assigned to receive 3 cycles of camrelizumab (200 mg) plus chemotherapy (nab-paclitaxel, 130 mg/m2 or pemetrexed (for adenocarcinoma), 500mg/m2 plus platinum [cisplatin, 75 mg/m2; carboplatin, area under the curve, 5]). Radical surgery was performed within 4-6 weeks after neoadjuvant therapy. Patients undergo 18F-fluorodeoxyglucose (FDG) PET/CT scans within 1 week before treatment and surgery, respectively. The primary endpoints for follow-up are pathologic complete response (pCR) rate and major pathological response (MPR) rate, while secondary endpoints include safety and disease-free survival (DFS). Exploratory endpoints include molecular imaging research and biomarker analysis. Results: Up to December 2023, 30 patients (median age: 64 years) have been enrolled, including 22 cases of squamous carcinoma and 8 cases of adenocarcinoma. All patients received 3 cycles of neoadjuvant camrelizumab plus chemotherapy, and 27 patients underwent radical sugery. Three patients did not receive surgical treatment, 2 of whom refused surgery and 1 was unable to undergo surgery due to disease progression. Among patients received surgery, 27 (100%) achieved R0 resection, 10 (37.0%) achieved pCR, and 15 (55.6%) achieved MPR. For patients with squamous cell carcinoma, the MPR and pCR rates were 70% (14/20) and 45% (9/20), respectively, while for adenocarcinoma patients, the MPR and pCR rates were 14.3% (1/7) and 14.3% (1/7), respectively. There was no significant difference in pathological response rates between the PD-L1 tumor proportion score (TPS) ≥ 1% group and the PD-L1 TPS &lt; 1% group. Most of treatment-related adverse events (TRAEs) were grade 1-2, and the most common TRAEs was leukopenia (63.0%). Five patients (18.5%) developed grade ≥ 3 TRAEs, including 3 leukopenia, 1 neutropenia, and 1 pneumonia. Biomarker analysis showed that among patients with pCR, the proportion of increased circulating M1 macrophages and decreased mononuclear myeloid-derived suppressor cells (M-MDSCs) and M2 macrophages after treatment was higher than those in non-pCR patients. Circulating ctDNA analysis showed that the ctDNA concentration of patients with non-pCR after treatment was higher than that of patients with pCR. Patients with ctDNA remaining positive after treatment were all in the non-pCR group. Conclusions: Neoadjuvant camrelizumab combined with chemotherapy for NSCLC patients show promising pathological response rates and tolerable safety. Clinical trial information: NCT06241807 .

MRI compared to 123I-MIBG scan for detection of central nervous system relapse in neuroblastoma.

10040 Background: Neuroblastoma (NB) relapsing in the central nervous system (CNS), though uncommon, is historically incurable. However, a multimodality approach has improved long term survival (1). Timely detection of CNS relapse may reduce or prevent morbidity and mortality. In most centers, surveillance for NB includes whole-body MIBG scans but does not require dedicated anatomical brain imaging. At Memorial Sloan Kettering Cancer Center (MSK), head MRI at regular intervals is standard. The objective of this retrospective study was to determine the optimal imaging modality for detecting CNS relapse in NB. Methods: After MSK IRB approval, records of patients with CNS NB seen at MSK from 2004-2023 were evaluated. In most cases, relapse was diagnosed at other institutions before referral to MSK. Analyzed data included symptoms and findings on brain CT/MRI and MIBG scans. Results: Of 206 patients with MIBG-avid CNS NB, 7 were excluded because they had CNS disease at diagnosis. For the remaining 199 patients, median time to CNS relapse from diagnosis was 18 months. 132 (66%) patients had CNS relapse at a median of 9.8 months after achieving complete remission. In 67 patients with prior systemic progression, median time to CNS relapse was 10.9 months from the last relapse. Relapse was isolated to CNS in 130/199 (65%) patients. 118 (59%) patients had neurological symptoms at time of CNS disease; 81(41%) were asymptomatic, relapse being detected on surveillance scans. Multiple (&gt;1) parenchymal lesions were noted in 74 (37%), diffuse leptomeningeal disease without parenchymal involvement in 15 (7%) and solitary lesions in 110 (55%) patients. Median diameter of the largest lesion was 2.7 (range &lt;0.5-6.8) cm. Anatomical imaging was performed with MRI (65%), CT (14%) or both (34%). Of those undergoing both scans, CNS relapse was missed on CT in 4/67 (6%) patients. 137 patients had MIBG scans before resection of CNS relapse. All sites of CNS disease noted on MRI/CT were positive by MIBG in 46 (33%) patients. However, MIBG scan was either totally or partly negative in 69 (50%) and 22 (16%) patients, respectively. Even for lesions ≥2cm in diameter, MIBG was completely negative in 27/57 (47%). MIBG positivity did not correlate with age, size &gt;2cm, MYCN amplification or ALK mutation status (p&gt;0.05 for each). Lesions &lt;1cm and infratentorially located were more likely to be negative on MIBG scan (p&lt;0.05). Lesions in symptomatic patients, dural lesions and hemorrhagic lesions were more likely to be positive on MIBG scan (p&lt; 0.05). Conclusions: CNS relapse is isolated to the brain in most patients. MIBG scan has poor sensitivity for the detection of CNS NB, regardless of size or location. Although CT or MRI are both effective in detecting CNS relapse, the former can miss some lesions. We recommend brain MRI for surveillance of high-risk NB for ≥2 years after initial diagnosis or last systemic relapse. 1. J. Neurooncology 97:409, 2010.

A biomarker-directed, multi-center phase II/III study of ctDNA molecular response adaptive immuno-chemotherapy in patients with non-small cell lung cancer.

TPS8669 Background: Liquid biopsy analyses of circulating cell-free tumor DNA (ctDNA) have shown promise as an early endpoint of immunotherapy response, allowing patients with primary resistance to be rapidly and accurately identified. BR.36 is a ctDNA-directed, phase II/III trial of molecular response-adaptive immuno-chemotherapy; in the first of two independent stages, the BR.36 trial met its primary endpoint, with a sensitivity of ctDNA response for radiographic RECIST response of 82% and a specificity of 75%, while demonstrating a median time to ctDNA response of 2.1 months. Additionally, patients with ctDNA molecular response attained longer progression-free (PFS) and overall survival (OS). Methods: The second stage of BR.36 is a multi-center, biomarker-directed, phase II/III clinical trial of ctDNA molecular response adaptive immuno-chemotherapy in patients with immunotherapy and chemotherapy-naïve metastatic NSCLC. The main objective is to evaluate if adding chemotherapy to pembrolizumab for patients who have persistent ctDNA on liquid biopsy drawn after 6 weeks of treatment will result in better PFS and OS compared to patients who remain on pembrolizumab until clinical progression. Key eligibility criteria include: age ≥18 years, ECOG performance status 0-2, metastatic NSCLC, EGFR and ALK mutation negative and PD-L1 Tumor Proportion Score (TPS) ≥ 50%, at least and not more than 2 cycles of the 200 mg or 2 mg/kg IV Q3W of pembrolizumab as first line systemic immunotherapy at the time of screening and RECIST non-PD or clinically stable PD documented prior to enrolment that can continue on immunotherapy. The phase II primary endpoint is PFS and has secondary endpoints of feasibility, overall response rate and safety/tolerability. Sex, RECIST response and ECOG status represent stratification criteria. With 110 randomized patients evaluable for progression (55 patients per arm and 71 PFS events observed in this phase), we would be able to detect a hazard ratio difference of 0.67 with a 1-sided alpha of 0.2 and power of 0.80 using a phase II screening design. The trial will not stop accrual for the phase II analysis of PFS if feasibility endpoints are achieved. In the phase III portion, a total of 210 randomized patients recruited over 3 years and followed for an additional 24 months are required to detect an OS hazard ratio difference of 0.67 with 1-sided alpha of 0.05 and power of 0.8. The total number of events for the final analysis is 156, and assuming 10% of patients are lost to follow-up, we are targeting 230 patients to be included overall. The primary endpoint of the phase III portion is OS, with secondary endpoints of best overall response, response duration, PFS and safety/tolerability. Exploratory endpoints include longitudinal ctDNA analyses. The BR.36 clinical trial is open to enrollment (ClinicalTrials.gov ID: NCT04093167). Clinical trial information: NCT04093167 .

Mucinous epidermoid carcinoma of the lung with ALK mutation: Case report and literature review.

Pulmonary mucoepidermoid carcinoma (PMEC) is a rare lung malignancy, especially in combination with ALK mutations, whose clinical presentation lacks specificity and for which there are no standardized treatment guidelines. We report a case of a patient with PMEC-predominant primary lung cancer combined with an ALK mutation. One patient was diagnosed with PMEC combined with ALK mutation. After diagnosis by puncture pathology, the patient was treated with oral targeted drugs. The patient's cough and fever were controlled, her diet improved significantly, and she gained 20 pounds in 6 months. During this period, the primary and metastatic foci in the lungs were significantly reduced on repeat chest CT. PMEC combined with ALK mutation is an extremely rare primary lung cancer, and the diagnosis is mainly based on pathology, histology and immunohistochemistry. The application of molecularly targeted drugs to patients with mutations can significantly improve the prognosis of patients with PMEC, which is expected to be a new breakthrough in the treatment of PMEC.

A comprehensive analysis of POLE/POLD1 genomic alterations in colorectal cancer.

Pathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H), defined as TMB ≥ 10 mut/Mb, independent of deficient mismatch repair (dMMR) and microsatellite instability high (MSI-H) status. De-identified records of patients with colorectal cancer (CRC) profiled with the Tempus xT assay (DNA-seq of 595-648 genes at 500×) were identified from the Tempus Database. Among 9136 CRC samples profiled, the frequency of POLE/POLD1 genomic alterations was 2.4% (n = 217). Copy number loss was the most common genomic alteration (64%, n = 138) of POLE/POLD1, followed by copy number amplifications (18%, n = 40) and short variant mutations (18%, n = 39). The POLE/POLD1 mutated group presented with a higher frequency of TMB-H phenotype relative to wild type (WT; 22% vs. 9%, P < .001), with a median TMB of 127 mut/Mb in the TMB-H POLE/POLD1 subset. The TMB showed a dramatic contrast between POLE/POLD1 short variant mutations as compared to the group with copy number alterations, with a TMB of 159 mut/Mb vs 15 mut/Mb, respectively. Thus, the short variant mutations represented the so-called ultra-hypermutated phenotype. The POLE/POLD1 mutated group, as compared to WT, exhibited a higher rate of coexisting mutations, including APC, ALK, ATM, BRCA2, and RET mutations. Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers (ie, TMB, MMR, and MSI-H) and molecular co-alterations. Those with short variant mutations represented 18% of the POLE/POLD1 cohort and 0.4% of the total cohort examined. This group of patients had a median TMB of 159 mut/Mb (range 34-488), representing the ultra-hypermutated phenotype. This group of patients is important to identify given the potential for exceptional response to immune checkpoint inhibitors.

Management of High-Risk Neuroblastoma with Soft-Tissue-Only Disease in the Era of Anti-GD2 Immunotherapy.

Neuroblastoma presents with two patterns of disease: locoregional or systemic. The poor prognostic risk factors of locoregional neuroblastoma (LR-NB) include age, MYCN or MDM2-CDK4 amplification, 11q, histology, diploidy with ALK or TERT mutations, and ATRX aberrations. Anti-GD2 immunotherapy has significantly improved the outcome of high-risk (HR) NB and is mostly effective against osteomedullary minimal residual disease (MRD), but less so against soft tissue disease. The question is whether adding anti-GD2 monoclonal antibodies (mAbs) benefits patients with HR-NB compounded by only soft tissue. We reviewed 31 patients treated at SJD for HR-NB with no osteomedullary involvement at diagnosis. All tumors had molecular genetic features of HR-NB. The outcome after first-line treatment showed 25 (80.6%) patients achieving CR. Thirteen patients remain in continued CR, median follow-up 3.9 years. We analyzed whether adding anti-GD2 immunotherapy to first-line treatment had any prognostic significance. The EFS analysis using Cox models showed a HR of 0.20, p = 0.0054, and an 80% decrease in the risk of relapse in patients treated with anti-GD2 immunotherapy in the first line. Neither EFS nor OS were significantly different by CR status after first-line treatment. In conclusion, adding treatment with anti-GD2 mAbs at the stage of MRD helps prevent relapse that unequivocally portends poor survival.

LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion

The CLIP1-LTK fusion was recently discovered as a novel oncogenic driver in non-small cell lung cancer (NSCLC). Lorlatinib, a third-generation ALK inhibitor, exhibited a dramatic clinical response in a NSCLC patient harboring CLIP1-LTK fusion. However, it is expected that acquired resistance will inevitably develop, particularly by LTK mutations, as observed in NSCLC induced by oncogenic tyrosine kinases treated with corresponding tyrosine kinase inhibitors (TKIs). In this study, we evaluate eight LTK mutations corresponding to ALK mutations that lead to on-target resistance to lorlatinib. All LTK mutations show resistance to lorlatinib with the L650F mutation being the highest. In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance.

Clinical and Therapeutic Characteristics of Hospitalized Patients with Advanced Lung Cancer in Najran, Saudi Arabia: A Retrospective Study.

Lung cancer is one of the top causes of cancer deaths globally, including in Saudi Arabia. Although several prognostic markers have been established, the clinical features and outcomes of lung cancer in Saudi Arabia are not well understood. This study aimed to describe the clinical and therapeutic characteristics of advanced lung cancer in Najran, SaudiArabia. A retrospective chart review of 44 patients diagnosed with advanced lung cancer between June 2018 and September 2021 and treated at the Oncology Center of King Khalid Hospital in Najran City, Saudi Arabia. The clinicopathological features, treatment used, response, and survival outcomes were collected and analyzed. The mean age was 69.3 ± 10.7 years, most of them (n = 35, 79.5%) were male and older than 70 years (n = 24, 54.5%). Adenocarcinoma was the most observed cancer (n = 35, 79.5%), followed by squamous cell carcinoma in six (13.6%). Most cases (n = 42, 95.5%) were in stage IV. Epidermal growth factor receptor (EGFR) mutations were positive in two (4.5%) cases and ALK mutation was positive in two (4.5%) cases. Metastasis to pleura with pleural effusion was the common presentation (n = 41, 93%). Chemotherapy was administered as the first line in 19 cases (43.2%) while 25 cases (56.8%) received chemoimmunotherapy. The commonest chemoimmunotherapy regimen used was carboplatin-pemetrexed-pembrolizumab in 16 (36.4%), followed by carboplatin-paclitaxel-pembrolizumab in 9 (20.5%) cases. The response to initial systemic therapy was as follows disease progression, stable disease, and complete remission in 10 (22.7%), 33 (75.0%), and 1 (2.3%), respectively. Median progression-free survival was 8.7 months (interquartile range (IQR): 5.7-11.4), and the median overall survival was 12.3 months (IQR: 11.1-13.4). Among the total documented 36 (81.8%) dead cases, disease progression was the main cause of death in 25 cases (56.8%). Using chemoimmunotherapy as the first-line therapy was associated with numerical survival improvement compared to using chemotherapy alone (HR: 0.75; 95% CI: 0.39-1.46) however, it was not statistically significant (p = 0.397). In this study, the majority of lung cancer patients were male and over 70 years old. Adenocarcinoma was the most common histological type. Metastasis to pleura with pleural effusion was the common presentation. The most common treatment used was chemoimmunotherapy with a regimen of carboplatin-pemetrexed-pembrolizumab. Addressing the possible causes of delayed diagnosis of lung cancer is crucial for improved survival outcomes.

Comparative study of imaging and pathology of primary mucinous adenocarcinoma with different imaging manifestations.

Pulmonary mucinous adenocarcinoma is a special type of lung cancer. Its imaging manifestations are diverse, which brings challenges to clinical diagnosis. However, its formation mechanism is unclear. The objective of this study is to analyse the relevant mechanisms of the formation of pulmonary mucinous adenocarcinoma by observing its different imaging and pathological manifestations. Retrospective analysis was conducted on imaging manifestations and pathological data of 103 patients with pulmonary mucinous adenocarcinoma confirmed intraoperatively or pathologically. Forty-three patients had pulmonary mucinous adenocarcinoma with a solitary nodule/mass, 41 patients with localized pneumonia and 19 patients with diffuse pneumonia. Their CT manifestations included 'falling snowflake sign', ground-glass opacity close to the heart, vacuous signs/honeycombing and withered tree branches. Under the microscope, all the three types of pulmonary mucinous adenocarcinoma had visibly formed mucus lakes but were made of tumour cells with totally different shapes, which included the goblet-like shape (tall column-like shape) and quasi-circular shape. Tall column-shaped tumour cells were negative or weakly positive for thyroid transcription factor-1 (TTF-1) and strongly positive for ALK mutation, whereas quasi-circular tumour cells were positive for TTF-1 and less positive for ALK mutation. The different imaging manifestations of mucinous adenocarcinoma are possibly due to the different amounts or viscosity of mucus produced, and the mechanisms of its formation may include (1) tumour cells in different shapes have different abilities to produce mucus; (2) tumours in different stages produce different amounts or viscosity of mucus; and (3) the TTF-1 and ALK genes affect the production of mucus.

ALK-mutated thyroid cancer

At the moment, the standard of treatment in the Russian Federation for late stages of well-differentiated thyroid cancer (hereinafter referred to as WDTC) with a recorded radioiodine-resistant tumor status is the sequential administration of multikinase inhibitors: Sorafenib, Lenvatinib. Treatment protocols for subsequent lines have not been developed. The purpose of this article is to review the main molecular genetic features of WDTC and present the clinical observation of a patient with metastatic radioiodine-resistant follicular varient of papillary thyroid cancer (hereinafter referred to as PTC), which has progressed after previous lines of therapy. The patient’s tumor biological material was submitted for next-generation sequencing (NGS), which allows detection of all classes of molecular changes for a large number of genes. Due to the discovery of an ALK mutation and the lack of registered standards for subsequent treatment, ALK inhibitors were prescribed. This attempt to individualize therapy was successful: a partial response was registered during therapy and a significant clinical improvement in the patient’s general condition was noted. Therapy with ALK inhibitors continues to this day (46 months as of October 2023) and has a favorable toxicity profile. Thus, we can conclude that when the basic standards for the treatment of metastatic well-differentiated thyroid cancer have been exhausted, there is an individual selection of targeted therapy depending on the molecular genetic characteristics of the tumor process.

Abstract 6254: Casein kinase II (CK2) expression in pediatric solid tumors

Abstract Despite recent advances, high-risk neuroblastoma (NB) and sarcomas account for 15% and 5% of all pediatric cancer deaths, respectively. Many patients attain remission, but approximately half of patients relapse. Genomic alterations such as MYCN amplification and ALK mutations have been shown to be important in prognosis and treatment. Despite improvements, approximately 20% of patients have refractory or recurrent disease after therapy, underscoring the need for further genomic understanding and new approaches to treatment.CK2 is a serine/threonine kinase that regulates numerous cellular processes such as cell growth, proliferation, and survival. Overexpression of CK2 is associated with a poor prognosis in several adult solid tumors, making it a potential target of interest in pediatric solid tumors. This study aims to investigate CK2 expression among patients with NB, Ewing sarcoma (EWS), and rhabdomyosarcoma (RMS) and its correlation with patient survival. MethodsPatients were enrolled in NMTRC008/009: “Feasibility Trial Using Molecular Guided Therapy for Patients with Relapsed/Refractory Childhood Cancer” and BCC-001. WES and RNA-Seq were performed at the Translational Genomics Research Institute and Sema4 or Caris respectively. RNA expression levels were compared to a normal whole-body reference and a pediatric cancer reference. Differential expression data were interpreted in the context of systems biology.ResultsTumor WES was performed on 297 patients (212 NB, 50 EWS, 35 RMS) and RNA-Seq on 284 patients (210 NB, 39 EWS, 35 RMS). The most common mutations or copy number alterations were seen in MYCN, ATRX, ALK, CDKN2A, and chr17q+ in NB; EWSR1-FLI1 fusion in EWS; PAX3-FOXO1 fusion in RMS. RNA expression analysis was performed to understand MYCN-driver status by covariance and interactions and to identify subsets of patients with high/low expression of CK2 in different tumors. CK2 bimodal expression is seen across various cancers and normal tissues, implying distinct sub-groups exist in the data. In NB, overexpression of the CK2 gene with statistical significance was found in MYCN-amplified and chr17q+ tumors. A positive and negative correlation of the CK2 gene is seen with several target genes like MYCN, TRIM71, LIN28B, and HMGA2, JAK2, AR, STAT3, EGFR, LEF1, and NFKB2, respectively. In EWS and RMS, subgroups are identified with high and low expression of the CK2 gene.ConclusionGenomic sequencing of pediatric solid tumors showed a low mutation burden. RNA analysis resulted in the identification of potential novel therapeutic targets involving CK2 pathways. High expression of CK2 correlates with MYCN status. Further analysis of patient molecular subgroups is ongoing. Citation Format: Abhinav Beeravally Nagulapally, Chandrika Behura, Divya Gandra, Giselle Saulnier Sholler. Casein kinase II (CK2) expression in pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6254.