Metastatic Non-small Cell Lung Research Articles

Association of KRAS G12D vs. G12V circulating tumor DNA variant allele fraction and real-world overall survival in metastatic non-small cell lung and colorectal cancers.

3041 Background: We previously reported KRAS G12D but not G12V variant allele fraction (VAF), as measured in circulating tumor DNA (ctDNA), was associated with overall survival (OS) in metastatic treatment-naïve pancreatic cancer (mPDAC). However, this has not been examined in other RAS-driven cancers. Here we assessed association of real-world OS (rwOS) with KRAS G12D and G12V VAF in metastatic colorectal cancer (mCRC) and non-small cell lung cancer (mNSCLC). Methods: We queriedGuardantINFORM, a real-world evidence database of aggregated commercial payer health claims and de-identified results from Guardant360 (G360) ctDNA testing from 2014 to 2023, to identify mNSCLC/mCRC patients who were treatment-naive and had KRAS G12D or G12V mutations identified < 30 days prior to first-line therapy initiation. Those with co-occurring KRAS alterations, KRAS amplifications, and/or MSI-H were excluded. Outcomes were assessed as above vs. below median VAF and stratified by treatment type. The Cox regression model was run for continuous VAF, adjusting for age, gender, summary comorbidity score [Elixhauser Comorbidity Index (ECI)], and year of G360. Results: For mCRC, KRAS VAF above median was significantly associated with shorter rwOS for both G12D and G12V (Table 1); subgroup analysis of the predominant standard-of-care chemotherapy, FOLFOX, showed similar findings. For mNSCLC, KRAS VAF above median was associated with shorter rwOS for G12V, but not G12D (Table). Subgroup analysis by first-line treatment type revealed this association to be similar for chemotherapy-containing regimens but not immunotherapy (IO) alone. Conclusions: While a variant-specific association of KRAS VAF with rwOS was observed in mNSCLC overall (G12V associated, G12D not), above vs below median VAF was not associated with rwOS for the subset of patients receiving IO only. In contrast, for mCRC both G12D and G12V VAF were associated with rwOS, including for the subset of patients who received chemotherapy. These data suggest a complex interplay between KRAS variant, ctDNA shedding, first-line treatment, and OS that will be important in the interpretation of the prognostic implications of ctDNA-identified KRAS alterations. [Table: see text]

Clinical outcomes of chemotherapy rechallenge in patients with metastatic non-small cell lung (NSCLC) who progressed on immunotherapy maintenance after front line platinum doublets and immunotherapy.

e21205 Background: Maintenance immunotherapy (IO) is commonly utilized in metastatic NSCLC patients (pts) who did not progress after initial treatment with platinum doublet and IO. Upon progression, docetaxel with or without ramucirumab remains the treatment of choice, which is associated with poor response and high toxicity. We explored the option of rechallenge of original chemotherapy agents in this patient population. Methods: We queried MD Anderson Cancer Center GEMINI database to perform a retrospective review in pts who received chemotherapy (chemo) rechallenge with or without IO after progression on or after IO maintenance from 03/2016 – 12/2022 at MD Anderson Cancer Center. We assessed clinical response and progression free survival (PFS) with initial triplet treatment and rechallenge with chemotherapy. Clinical response was defined as clinical benefit based on clinician’s radiographic and clinical assessment. PFS was defined as the time interval free of disease progression. Demographics and results were summarized with descriptive statistics. Results: 20 patients received chemo rechallenge with or without IO after progression on IO maintenance. Upon chemo rechallenge, 7 pts received pemetrexed; 10 pts (50%) received carboplatin and pemetrexed; 19 pt received chemo rechallenge with IO. Median duration of initial IO maintenance was 9.4 months. Median duration of chemo rechallenge was 5.2 months. 10 (50%) pts discontinued chemo due to progression after receiving chemo rechallenge; 2 (10%) pts discontinued chemo rechallenge due to toxicities; 3 (15%) pts remained on therapy at the data cutoff of 2/10/2023. Median PFS with initial triplet was 14.3 months. Median PFS with chemo rechallenge was 7.4 months, longer than the histological control of 3-5 months from docetaxel +/- ramucirumab. Conclusions: Our single center retrospective review demonstrated that chemo rechallenge after progression on IO maintenance post front-line chemo-IO therapy had good tolerability and reasonable PFS, which may offer a reasonable alternative option to docetaxel+/-ramucirumab. Future studies are needed to confirm this result using docetaxel +/- ramucirumab as a control. [Table: see text]

The impact of novel therapies on disparities in survival outcomes for metastatic cancers.

e18635 Background: Real-world data have suggested that increases in overall survival (OS) for metastatic cancers over time have been driven by improvements in the groups of patients who already had the highest survival outcomes. To further investigate these identified trends, this research aimed to quantify how novel therapies for metastatic cancers impact disparities in OS outcomes. Methods: Novel therapies for metastatic breast (mBC), metastatic colorectal (mCRC), and metastatic non-small cell lung (mNSCLC) cancer, approved by the United States Food and Drug Administration (FDA) in the last 8 years based on data from phase III randomised controlled trials (RCTs), were identified. For each cancer type, 3 novel therapies were selected with inclusion based on the availability of published Kaplan-Meier data for OS, at least 100 patients in each arm of the corresponding RCT, and OS reaching less than 30% at the end of the RCT follow-up period. For each cancer type and for the novel therapies and comparator therapies separately, the published OS data were replicated from the Kaplan-Meier data and pooled using weights based on sample sizes to ensure each therapy contributed equally to the analysis. Parametric survival modelling was performed to address censoring. The disparity in OS was defined by the absolute difference between groups with the highest and lowest survival, with groups defined by stratifying OS in either 2 or 5 groups. The impact of the combined novel therapies was determined based on the change in OS disparity relative to the combined comparators. A probabilistic analysis was performed to quantify the impact of parameter uncertainty on the outcomes. Results: Novel therapies increased disparities in OS across the 3 cancers. For mBC, the disparities in OS increased by 5.4 (95%-confidence interval: 0.9; 9.9) months, which equates to a 23.0% increase from 24.2 to 29.6 months if OS was stratified in 2 groups, and by 13.9 (1.4; 26.6) months; 25.0% from 57.1 to 71.1 if OS was stratified in 5 groups. For mCRC, disparities increased by 2.8 (1.4; 4.2) months; 37.6% from 7.5 to 10.3 months and by 6.3 (2.9; 9.8) months; 38.9% from 16.5 to 22.8 months, for stratification based on 2 and 5 groups, respectively. For mNSCLC, disparities increased by 10.2 (3.3; 17.3) months; 33.6% from 31.0 to 41.3 months and by 19.5 (4.0; 35.5) months; 31.5% from 63.2 to 82.7 months, for stratification based on 2 and 5 groups, respectively. Conclusions: OS outcomes for recent FDA-approved drugs for metastatic cancers suggest that these novel therapies increase disparities in OS between the patient groups with the highest and lowest OS relative to their comparator therapies in RCTs. Although evidence in terms of these disparities is important, further research using (real-world) individual patient data is warranted to assess how, for example, socioeconomic variables affect the impact of therapies on health disparities among patient groups.

Utility of the Khorana and the new-Vienna CATS prediction scores in cancer patients of the HYPERCAN cohort

BackgroundRisk assessment models (RAMs) are relevant approaches to identify cancer outpatients at high risk of venous thromboembolism (VTE). Among the proposed RAMs, the Khorana (KRS) and the new-Vienna CATS risk scores have been externally validated in ambulatory patients with cancer. ObjectivesTo test KRS and new-Vienna CATS scores in 6-month VTE prediction and mortality in a large prospective cohort of metastatic cancer outpatients during chemotherapy. Patients/MethodsNewly diagnosed patients with metastatic non-small cell lung, colorectal, gastric, or breast cancers were analyzed (n = 1286). The cumulative incidence of objectively confirmed VTE was estimated with death as a competing risk and multivariate Fine and Gray regression. ResultsWithin 6 months, 120 VTE events (9.7%) occurred. The KRS and the new-Vienna CATS scores showed comparable c-stat. Stratification by KRS provided VTE cumulative incidences of 6.2%, 11.4%, and 11.5% in the low-, intermediate-, and high-risk categories, respectively (p = ns), and of 8.5% vs. 11.8% (p = ns) in the low- vs. high-risk group by the single 2-point cut-off value stratification. Using a pre-defined 60-point cut-off by the new-Vienna CATS score, 6.6% and 12.2% cumulative incidences were obtained in the low- and high-risk groups, respectively (p < 0.001). Furthermore, having a KRS ≥2 = or a new-Vienna CATS score >60 points was also an independent risk factor for mortality. ConclusionIn our cohort, the 2 RAMs showed a comparable discriminating potential; however, after the application of cut-off values, the new-Vienna CATS score provided statistically significant stratification for VTE. Both RAMs proved to be effective in identifying patients at increased risk of mortality.

Anti-Tumor Activity of Orally Administered Gefitinib-Loaded Nanosized Cubosomes against Colon Cancer

Gefitinib (GFT) is a tyrosine kinase inhibitor drug used as a first-line treatment for patients with advanced or metastatic non-small cell lung, colon, and breast cancer. GFT exhibits low solubility and hence low oral bioavailability, which restricts its clinical application. One of the most important trends in overcoming such problems is the use of a vesicular system. Cubosomes are considered one of the most important vesicular systems used to improve solubility and oral bioavailability. In this study, GFT cubosomal nanoparticles (GFT-CNPs) were prepared by the emulsification method. The selected formulation variables were analyzed and optimized by full factorial design and response surface methodology. Drug entrapment efficiency (EE%), transmission electron microscopy, particle size, polydispersity index, in vitro release and its kinetics, and the effect of storage studies were estimated. The chosen GFT-CNPs were subjected to further investigations as gene expression levels of tissue inhibitors of metalloproteinases-1 (TIMP-1) and matrix metalloproteinases-7 (MMP-7), colon biomarkers, and histopathological examination of colon tissues. The prepared GFT-CNPs were semi-cubic in shape, with high EE%, smaller vesicle size, and higher zeta potential values. The in vivo data showed a significant decrease in the serum level of embryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and gene expression level of TIMP-1 and MMP-7. Histopathological examination showed enhancement in cancer tissue and highly decreased focal infiltration in the lamina propria after treatment with GFT-CNPs.

Abstract CT551: Randomized phase III study comparing the efficacy and safety of CT-P16, a new biosimilar, to reference bevacizumab (Avastin®) in patients with metastatic or recurrent non-small cell lung cancer (NSCLC)

Abstract Background: CT-P16 is a proposed biosimilar to FDA approved reference bevacizumab (BV), namely Avastin®. This trial (NCT03676192) compared the efficacy and safety of CT-P16 and BV in patients with metastatic or recurrent non-squamous NSCLC. Methods: This double blind, randomized, multicenter study randomly assigned patients to CT-P16 or BV with carboplatin and paclitaxel, up to 6 cycles (Induction Period), followed by maintenance CT-P16 or BV monotherapy until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) during the Induction Period. ORR includes complete or partial responses based on RECIST v1.1 assessed by an independent reviewer. Secondary endpoints were Quality of life (QoL), PK, safety, and immunogenicity. Results: A total of 689 patients were randomized (CT-P16: 342, BV: 347). The baseline characteristics were well balanced. ORRs were similar between the two treatment arms and the 90% confidence intervals (CIs) for the risk ratio estimate (0.7368, 1.3572) and 95% CIs for risk difference estimate (±12.5%) were within the equivalence margin in both ITT (intent-to-treat) and PP (per-protocol) sets. QoL results (QLQ-C30 and QLQ-LC13) and PK parameter (Ctrough) were comparable between the two treatment arms. The overall incidence of treatment-emergent adverse events (TEAEs), serious AEs (TESAEs), AEs leading to discontinuation, and AEs leading to death was similar between the two treatment arms (96.2% vs. 92.4%, 19.4% vs. 20.1%, 15.1% vs. 14.5%, and 6.4% vs. 6.4% for the CT-P16 and BV treatment arm, respectively). The incidence of treatment-emergent anti-drug antibodies was comparable (14.2% vs. 16.0%). Conclusions: This study demonstrated that CT-P16 is equivalent to BV as measured by ORR in patients with metastatic or recurrent adenocarcinoma of the lung. Other endpoints including PK, QoL, safety and immunogenicity were comparable. Primary endpoint ITT PP CT-P16 (N=342) BV (N=347) CT-P16 (N=318) BV (N=303) Independent reviewer ORR (%) 95% CI 42.40 (37.16 - 47.64) 42.07 (36.88 - 47.27) 45.28 (39.81 - 50.75) 47.19 (41.57 - 52.82) Risk ratio estimate (90% CI) 1.0136 (0.8767, 1.1719) 0.9662 (0.8387, 1.1132) Risk difference estimate (%) (95% CI) 0.40 (-7.02, 7.83) -1.90 (-9.80, 6.00) Investigator ORR (%) 95% CI 43.86 (38.60 - 49.12) 39.19 (34.06 - 44.33) 46.54 (41.06 - 52.02) 43.89 (38.31 - 49.48) Risk ratio estimate (90% CI) 1.1234 (0.9683, 1.3032) 1.0648 (0.9209, 1.2313) Risk difference estimate (%) (95% CI) 4.87 (-2.53, 12.26) 2.90 (-4.99, 10.79) Citation Format: Yuichiro Ohe, Igor Bondarenko, Zoran Andric, Yuriy Ostapenko, Tudor Ciuleanu, Fedor Moiseenko, Tamta Makharadze, Sergii Shevnya, Alona Oleksiienko, Eduardo Yañez Ruiz, SungHyun Kim, KeumYoung Ahn, TaeHong Park, Sijin Park, JiEun Lee, MinJi Kim, Claire Verschraegen. Randomized phase III study comparing the efficacy and safety of CT-P16, a new biosimilar, to reference bevacizumab (Avastin®) in patients with metastatic or recurrent non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT551.

Abstract 3260: Enhanced lineage plasticity in RTK-independent TKI-resistant EGFR-mutant NSCLC

Abstract Background: Resistance to targeted tyrosine kinase inhibitors (TKI) inevitably develops in metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Resistance mechanisms are diverse, and mechanisms beyond receptor tyrosine kinase (RTK) pathway mutations are poorly understood. We hypothesized that the use of osimertinib as first-line therapy is increasing the prevalence of RTK-independent resistance mechanisms, and that RTK-independent resistant tumors undergo enhanced tumor cell lineage plasticity as an escape mechanism to EGFR TKI therapy. Methods: We identified patients who developed osimertinib resistance (OR) after first line (1L, n=54) and second line (2L, n=42) treatments and determined the resistance mechanisms based on clinical sequencing and histopathology. We also performed single-cell RNA-seq of 24 samples from 13 patients with EGFRm NSCLC at TKI treatment-naïve (TN, n=2), residual disease (RD, n=4), and progression disease (PD, n=7) stages. Results: Compared to 2L OR tumors, 1L OR tumors had increased RTK-independent mechanisms of resistance (76% vs. 46%, p=0.002), including 8% with small cell transformation (n=4), 2% with squamous transformation (n=1) and 66% with unknown mechanisms (n=34). To understand inter- and intra-tumor heterogeneity, we analyzed transcriptomic profiles of 76,266 single cells. Lung developmental lineages were assigned to 10,250 EpCAM+ cells, including 4,735 cells classified as malignant cells by inferCNV and RTK signaling analysis. In the two EGFRm TN tumors, the malignant cells demonstrated bronchoalveolar lineage and moderate EGFR expression. In the TKI resistant cases (PD, n=7), both RTK-dependent and RTK-independent resistance were observed. The RTK-dependent tumors (EGFR T790M n=1; ERBB2 amplification n=1) demonstrated preserved bronchoalveolar lineage identity. In the RTK-independent resistant tumors (n=5), one had complete lineage switch from epithelial to small cell neuroendocrine and very low expression level of EGFR. The remaining 4 PD tumors displayed varying expression of epithelial-to-mesenchymal transformation (EMT) features. One tumor had sarcomatoid histology and a high proportion of cells having positive VIM expression (84%) and 92% of cells having complete loss of NAPSA expression; 3 tumors had partial EMT demonstrated by heterogeneous proportion of cells having VIM expression (18-56%) and loss of NAPSA (26-67%). Interestingly, some of the cells with EMT and partial-EMT had moderate levels of EGFR expression, similar to the levels in the TN tumors. Conclusion: With osimertinib use at 1L, the incidence of RTK-independent resistance has increased to become the dominant mechanism, whereas RTK-dependent resistance has decreased. Increased lineage plasticity (small cell neuroendocrine, squamous and EMT) potentially serves as an RTK-independent TKI-resistance mechanism in EGFRm NSCLC. Citation Format: Xiuning Le, Ruiping Wang, Natalie Vokes, Yasir Elamin, Neda Kalhor, Daniel McGrail, Yuanxin Xi, Santiago Treviño III, Lingzhi Hong, Robyn Du, George Blumenschein, Carl Gay, Marcelo Negrao, Mehmet Altan, Hai Tran, Limei Hu, Jing Wang, Simon Heeke, Monique Nilsson, Jacqulyne Robichaux, Minghao Dang, Guangchun Han, Lauren Byers, Anne Tsao, Boris Sepesi, Chantale Bernatchez, Jianjun Zhang, Linghua Wang, John Heymach. Enhanced lineage plasticity in RTK-independent TKI-resistant EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3260.

Clinical efficacy of osimertinib in EGFR-mutant non-small cell lung cancer with distant metastasis

BackgroundOsimertinib—the third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)—has been widely used as a first-line treatment for patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib demonstrated central nervous system activity in patients with brain metastasis; however, its efficacy against other distant metastatic organs, including bone and liver, remains unclear. Therefore, we retrospectively analyzed the clinical efficacy of osimertinib in these patients in comparison to other EGFR-TKIs.MethodsClinical data of patients with advanced NSCLC receiving gefitinib/erlotinib (n = 183), afatinib (n = 55), or osimertinib (n = 150) at five medical institutions were retrospectively assessed for progression-free survival (PFS), overall survival (OS), and best overall response rate (ORR).ResultsIn univariate and multivariate analyses, most distant metastases, including the brain and bone, were unrelated to the therapeutic efficacy of osimertinib, although liver metastasis and L858R mutation were independently associated with shorter PFS. PFS and OS in patients with liver metastases were significantly shorter than those in patients without liver metastases (PFS: 7.4 vs. 19.7 months, OS: 12.1 months vs. not reached, respectively). Osimertinib provided significantly longer PFS in patients with brain or bone metastasis and exon 19 deletion than the other EGFR-TKIs. The PFS of patients with liver metastases was not significantly different among the three EGFR-TKI groups. Furthermore, the ORR of osimertinib in patients with liver metastases was significantly attenuated, and the effectiveness was similar to 1st- or 2nd -generation EGFR-TKIs.ConclusionOsimertinib provided better clinical benefits than 1st- and 2nd-generation EGFR-TKIs for patients with EGFR-mutant NSCLC, particularly those with brain or bone metastases and exon 19 deletion; however, its efficacy against liver metastasis was remarkably attenuated. New therapeutic developments for patients with EGFR-mutant NSCLC with liver metastases are needed.

HER3 expression in metastatic colorectal cancer: Defining the clinicomolecular profile of an emerging target.

3588 Background: The success of tailored systemic therapies in treating distinct molecular subsets of patients (e.g., deficient mismatch repair, BRAF mutant, HER2 amplified) has spurred further exploration of novel targetable subsets within the heterogeneous landscape of metastatic colorectal cancer (mCRC). Human epidermal growth factor receptor 3 [HER3 (ErbB3)], a member of the HER (ErbB) receptor tyrosine kinase family, plays an important role in tumorigenesis and metastases and has emerged as a promising therapeutic target in a diverse array of cancers. For example, patritumab deruxtecan (U3-1402; HER3-DXd) is a HER3-directed antibody drug conjugate that has demonstrated clinically meaningful antitumor activity and acceptable safety profiles in metastatic breast cancer and EGFR-mutated non-small cell lung cancer. There is limited data, however, on the clinicopathological characterization of HER3 expression in mCRC. Methods: Tissue samples (surgical-metastatectomy) (N = 115) were obtained from a clinical cohort of patients (N = 99) with histologically proven mCRC and liver metastases who underwent liver resection with/without perioperative systemic chemotherapy. HER3 expression was analyzed on whole-mount preparations by immunohistochemistry (IHC). Staining was performed and visualized using the HER3 (D22C5) XP Rabbit-mAb (Cell Signaling Technology). Patients were categorized based on membranous intensity score as follows: Low with IHC 0 (absence of staining or staining in &lt; 10% of tumor cells), 1+ (faint/barely perceptible staining in ≥10% of tumor cells) or 2+ (weak to moderate staining in ≥10% of tumor cells), or High with IHC 3+ (strong staining in ≥10% of tumor cells). Clinicomolecular and treatment data, including gender, tumor sidedness, mutational status (RAS or BRAF), and prior chemotherapy were collected by review of patient electronic medical records. Chi-squared (or Fisher’s exact) test were used to determine associations between groups. Overall survival (OS) was calculated using Kaplan-Meier method and compared using log-rank tests. Results: Among 99 analyzed patients, 98 were evaluable for HER3 expression. Of these 25.5%, 26.5%, 40.8% and 7.2% showed HER3 IHC scores of 3+, 2+, 1+ and 0, respectively. No significant association was seen with HER3 expression and clinicopathological variables, mutational status, or prior treatment. Among patients with 2 samples analyzed from the same liver surgery, there was a moderate level of heterogeneity with concordance of 78.5% (kappa 0.43). Patients with high HER3 expression had poorer OS (5-year OS: 52%; median: 90.2 months) compared to low HER3 expression (5-year OS: 85%; median: not reached). Conclusions: In this large cohort of mCRC, HER3 expression was observed in 92.8% of patients and across diverse clinical and molecular features, supporting HER3 as a promising targetable biomarker in a large subset of mCRC.

Assessing effectiveness of first-line carboplatin, pemetrexed, and pembrolizumab in patients with recurrent/metastatic lung adenocarcinoma.

e21045 Background: Randomized clinical trial data support the addition of immune checkpoint inhibitors to standard first-line platinum-doublet in patients with recurrent/metastatic non-small cell lung cancer. In the landmark KN189 Trial in which patients received carboplatin or cisplatin in combination with pemetrexed and pembrolizumab, the updated analysis (Gadgeel et al, JCO 2020) reported a median overall survival of 22 months. To explore the translation of this clinical trial-proven efficacy to clinical effectiveness in routine practice, we sought to explore patient outcomes with the combination of pemetrexed, carboplatin, and pembrolizumab as initial therapy for patients with recurrent or metastatic non-squamous non-small cell lung cancer. Methods: At two large, urban, academic medical centers (Hackensack University Medical Center and Memorial Sloan Kettering Cancer Center), we reviewed patient treatment data to identify all patient all patients with recurrent/metastatic non-squamous non-small cell lung cancer who received carboplatin, pemetrexed, and pembrolizumab as initial therapy for recurrent/metastatic NSCLC from June 2017 to December 2020. Patients with EGFR mutations or ALK gene fusions were excluded. From the medical record, we obtained baseline clinical characteristics, patient treatments and duration, as well as overall survival. Results: We identified 523 patients treated with carboplatin/pemetrexed/pembrolizumab, with 399 events occurring during the observation period. Baseline characteristics: 47% women and median age 66 (Interquartile range 59-72). The median overall survival from start of therapy was 11 months (95% confidence interval 9-12 months). Conclusions: In routine clinical practice, initiation of chemotherapy + immune checkpoint inhibitor as first-line therapy for patients with recurrent/metastatic NSCLC led to shorter median overall survival than reported in clinical trials. To further evaluate this finding, we will explore patient baseline characteristics including performance status, comorbidities, organ function as well as explore outcomes of a historical cohort of patients administered carboplatin and pemetrexed.

Does concurrent COX inhibition and immune checkpoint blockade improve clinical outcomes in patients with metastatic renal cell carcinoma (mRCC)?

354 Background: Cyclooxygenase (COX) inhibition is postulated to restore the immune environment and synergizes with immune checkpoint inhibitors (ICI). The concurrent use of COX inhibitors (COXi) and ICI was associated with longer disease control in metastatic melanoma and non-small cell lung cancer. However, its role in mRCC remains unclear. Methods: We retrospectively reviewed 194 patients with mRCC treated with ICI (PD-(L)1 inhibitors +/- CTLA-4 inhibitors or TKIs) at Moffitt Cancer Center between 6/2014-7/2019. Concurrent use of COXi (aspirin [ASA] or NSAIDs) was defined as at least 3 weeks of COXi use during the first ICI course. Clinical characteristics of both arms were compared using Chi-squared or Kruskal-Wallis Rank Sum test. Time to progression (TTP) and Overall survival (OS) were compared using Kaplan Meier’s estimates. Univariate and multivariate Cox proportional hazards model was performed to evaluate the association between clinical factors, TTP, and OS. Results: Of 194 patients, 126 patients (64.9%) took COXi. Median age was 59.7 years and 80.4% were male. COXi arm had fewer patients with &lt; 1 year from diagnosis to systemic treatment (45.9% vs 69.5%, p=0.006) and more advanced age (median: 66 years vs 60 years, p=0.01). IDMC risk group, number of prior therapies, neutrophil to lymphocytes ratio were similar between both arms. Median TTP was 8 months (m) for COXi arm and 12m for ICI only (HR 1.38; 95% CI [0.98, 1.94]). Median OS was 27m for COXi arm and 33m for ICI only (HR 1.05, 95% CI [0.69, 1.59]). Early mortality rate (within 3m of ICI treatments) were similar between both arms. Conclusions: In contrast to melanoma and lung cancer, concurrent use of COXi and ICI did not improve TTP and OS in patients with mRCC. The dual blockade showed a trend for shorter TTP and OS. Further validation studies with larger cohorts are needed to confirm this finding.[Table: see text]

Neurocognitive functioning following lung cancer treatment: The PRO-Long Study.

This observational cohort study investigates neurocognitive functioning (NCF) and its associations with overall survival (OS), disease-free survival (DFS) and patient-reported psychological toxicities in locally-advanced and metastatic non-small cell lung (NSCLC) cancer patients receiving loco-regional radiotherapy and/or systemic therapy. Objective NCF data was collected with six psychometrically validated neurocognitive tests. Subjective NCF was assessed with the cognitive domain of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items. Psychological toxicity data was collected with the patient-reported outcomes version of the common terminology criteria for adverse events. Meaningful clinical important differences were determined for changes in NCF. Univariate Cox proportional hazards models and generalized linear models were used to determine statistical significance (p<0.01). In total, 50 patients were recruited. At baseline, 13 (26%) patients had an impaired objective NCF. Over time, deterioration was seen in 11% (n=3), 5% (n=1) and 6% (n=1) of patients at 2-3, 6 and 12months post-treatment. The OS of patients with a normal NCF at baseline was longer than those with an impaired baseline NCF (29.5 vs 17.1months). No statistical significance has been reached between NCF and OS (p=.353) nor NCF and DFS (p=.251). Objective NCF was not correlated with subjective NCF (p=.193), nor anxiety (p=.504), depression (p=.513), memory problems (p=.813) and concentration problems (p=.813). Systemic treatment and loco-regional radiotherapy may have a temporarily negative impact on NCF in a small proportion of locally-advanced and metastatic NSCLC. Baseline NCF could be a predictor for OS.

Pembrolizumab induced cardiotoxicity

Background: Pembrolizumab is a monoclonal antibody-based chemotherapy infusion, recently approved for unresectable or metastatic solid tumors with certain genetic anomalies. Discussion: Pembrolizumab is an IV infusion therapy for treating non-surgical or metastatic melanoma and non-small cell lung cancer. Multiple cardiac complications have been related to this drug, the mechanism is not precise, but a possibility is immune events involving the cytotoxic T-cell resulting in fibrosis of the cardiac cells. Conclusion: New oncologic medications have emerged with a potential reversible or irreversible cytotoxicity, including inflammation, dysfunction, or apoptosis that could represent a life-threatening condition. There is not enough data to establish proper therapy to avoid cardiotoxicity on monoclonal therapies, but an early approach and immunosuppressive therapy are thought to improve the outcome.

Pembrolizumab induced cardiotoxicity

Background: Pembrolizumab is a monoclonal antibody-based chemotherapy infusion, recently approved for unresectable or metastatic solid tumors with certain genetic anomalies. Discussion: Pembrolizumab is an IV infusion therapy for treating non-surgical or metastatic melanoma and non-small cell lung cancer. Multiple cardiac complications have been related to this drug, the mechanism is not precise, but a possibility is immune events involving the cytotoxic T-cell resulting in fibrosis of the cardiac cells. Conclusion: New oncologic medications have emerged with a potential reversible or irreversible cytotoxicity, including inflammation, dysfunction, or apoptosis that could represent a life-threatening condition. There is not enough data to establish proper therapy to avoid cardiotoxicity on monoclonal therapies, but an early approach and immunosuppressive therapy are thought to improve the outcome.

Incorporation of plasma-based next-generation sequencing to improve guideline-concordant molecular testing in patients with newly diagnosed metastatic nonsquamous non-small cell lung cancer.

14 Background: Current NCCN guidelines recommend comprehensive molecular profiling for all newly diagnosed patients with metastatic non-squamous NSCLC to enable the delivery of personalized medicine. We have previously demonstrated that incorporation of plasma based next-generation gene sequencing (NGS) improves detection of clinically actionable mutations in patients with advanced NSCLC (Aggarwal et al, JAMA Oncology, 2018). To increase rates of comprehensive molecular testing at our institution, we adapted our clinical practice to include concurrent use of plasma (P) and tissue (T) based NGS upon initial diagnosis. P NGS testing was performed using a commercial 74 gene assay. We analyzed the impact of this practice change on guideline concordant molecular testing at our institution. Methods: A retrospective cohort study of patients with newly diagnosed metastatic non-squamous NSCLC following the implementation of this practice change in 12/2018 was performed. Tiers of NCCN guideline concordant testing were defined, Tier 1: complete EGFR, ALK, BRAF, ROS1, MET, RET, NTRK testing, Tier 2: included above, but with incomplete NTRK testing, Tier 3: &gt; 2 genes tested, Tier 4: single gene testing, Tier 5: no testing. Proportion of patients with comprehensive molecular testing by modality (T NGS vs. T+P NGS) were compared using one-sided Fisher’s exact test. Results: Between 01/2019, and 12/2019, 170 patients with newly diagnosed metastatic non-Sq NSCLC were treated at our institution. Overall, 98.2% (167/170) patients underwent molecular testing, Tier 1: n = 100 (59%), Tier 2: n = 39 (23%), Tier 3/4: n = 28 (16.5%), Tier 5: n = 3 (2%). Amongst these patients, 43.1% (72/167) were tested with T NGS alone, 8% (15/167) with P NGS alone, and 47.9% (80/167) with T+P NGS. A higher proportion of patients underwent comprehensive molecular testing (Tiers 1+2) using T+P NGS: 95.7% (79/80) compared to T alone: 62.5% (45/72), p &lt; 0.0005. Prior to the initiation of first line treatment, 72.4% (123/170) patients underwent molecular testing, Tier 1: n = 73 (59%), Tier 2: n = 27 (22%) and Tier 3/4: n = 23 (18%). Amongst these, 39% (48/123) were tested with T NGS alone, 7% (9/123) with P NGS alone and 53.6% (66/123) with T+P NGS. A higher proportion of patients underwent comprehensive molecular testing (Tiers 1+2) using T+P NGS, 100% (66/66) compared to 52% (25/48) with T NGS alone (p &lt; 0.0005). Conclusions: Incorporation of concurrent T+P NGS testing in treatment naïve metastatic non-Sq NSCLC significantly increased the proportion of patients undergoing guideline concordant molecular testing, including prior to initiation of first-line therapy at our institution. Concurrent T+P NGS should be adopted into institutional pathways and routine clinical practice.

Abstract LB040: Targeting CD38 and PD-1 with isatuximab (Isa) plus cemiplimab (Cemi) in patients (pts) with advanced malignancies: Results from a Phase 1/2 open-label, multicenter study

Abstract Background: CD38 is implicated in noncanonical adenosine synthesis and its overexpression on tumor cells has been implicated in T-cell exhaustion and resistance to immune checkpoint blockade. Preclinical data suggest that concurrent treatment of anti-CD38 and anti-PD-1/PD-L1 antibodies substantially reduce primary tumor growth via suppressing acquired resistance to immune checkpoint blockade, and thus enhancing anti-PD-1/PD-L1 efficacy. Methods: This Phase 1/2 study (NCT03367819) enrolled pts with metastatic castration-resistant prostate cancer (mCRPC) or advanced non-small cell lung cancer (NSCLC). The primary objectives of Phase 1 were safety and tolerability of Isa (anti-CD38 monoclonal antibody) + Cemi (anti-PD-1 monoclonal antibody) in pts with mCRPC (naïve to anti-PD-1/PD-L1 therapy) or NSCLC (progressed on anti-PD-1/PD-L1-containing therapy). Phase 2 used a Simon's 2-stage design with response rate (RR) as the primary endpoint. An interim analysis was planned after the first 24 (mCRPC) and 20 (NSCLC) pts receiving Isa+Cemi were enrolled in Phase 2. Tolerability, immunogenicity, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed, including CD38, PD-L1, tumor-infiltrating lymphocytes in the tumor microenvironment (TME), and peripheral immune cell phenotyping. Results: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. All pts experienced ≥1 treatment-emergent adverse event. Grade ≥3 events occurred in 13 (54.2%) mCRPC pts and 12 (60.0%) NSCLC pts. Based on PCWG3 criteria, assessment of best overall response (BOR) with Isa+Cemi in mCRPC revealed no complete responses (CR), 1 unconfirmed partial response (PR) (4.2%), and 5 (20.8%) pts with stable disease (SD). Per RECIST 1.1, NSCLC pts receiving Isa+Cemi achieved no CR or PR, and 13 (65%) achieved SD. Isa+Cemi resulted in ~40% reduction in CD38+ tumor-infiltrating immune cells in post-therapy biopsies. The combination triggered a significant increase in peripheral activated and cytolytic T cells, but decreased NK cells. In addition, low baseline CD38 levels on tumor cells were observed in NSCLC pts who progressed on prior checkpoint inhibitor treatment. No significant modulation of Tregs or PD-L1 in the TME or CD38 expression on tumor cells was observed. Conclusions: The present study suggests that CD38 and PD-1 modulation by Isa+Cemi has a manageable safety profile, reduces CD38+ immune cells in the TME, and activates peripheral T cells; however, this was not associated with significant antitumor activity in these small cohorts of mCRPC and NSCLC pts. Citation Format: Chia-Chi Lin, Paolo Zucali, Bradley Carthon, Todd M. Bauer, Marcello Tucci, Antoine Italiano, Roberto Iacovelli, Wu-Chou Su, Christophe Massard, Monsoor Saleh, Gennaro Daniele, Alastair Greystoke, Martin Gutierrez, Shubham Pant, Ying-Chun Shen, Matteo Perrino, Robin Meng, Giovanni Abbadessa, Helen Lee, Yingwen Dong, Marielle Chiron, Rui Wang, Laure Loumagne, Johann de Bono, Johann de Bono. Targeting CD38 and PD-1 with isatuximab (Isa) plus cemiplimab (Cemi) in patients (pts) with advanced malignancies: Results from a Phase 1/2 open-label, multicenter study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB040.

The pre-clinical discovery and development of osimertinib used to treat non-small cell lung cancer

ABSTRACT Introduction: Osimertinib is currently the only FDA- and EMA-approved third-generation small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It was initially indicated for second-line treatment of patients with metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) and got approved for first-line treatment of EGFR activation mutation-positive metastatic NSCLC in 2018. Most recently, the FDA granted approval for the adjuvant treatment of patients with early-stage mutated EGFR NSCLC after tumor resection. Areas covered: This drug discovery case history focuses on the key studies that led to the preclinical discovery and development of osimertinib. The authors focus on published preclinical studies by scientists from AstraZeneca and highlight key events in the clinical development. Expert opinion: Although eventually compromised by the cellular plasticity of the tumor and the inevitable acquisition of drug resistance through the use of osimertinib, its key role in the treatment of NSCLC with specific EGFR mutations will be maintained in the near future. As the genome of EGFR is highly labile and since the rapid development of new mutants remains an issue, there is still room for improvement for the next generation of inhibitors.

Upfront thoracic radiotherapy to primary lession improve outcomes in patients with stage IV non-small cell lung cancer harboring EGFR mutations.

e21167 Background: The role of thoracic radiotherapy in the treatment of metastatic EGFR mutant non-small cell lung cancer patients in literature datas are insufficient.The aim of this study was to examine the effectiveness of upfront thoracic radiotherapy in metastatic EGFR mutant NSCLC patients treated with chemotherapy or TKI. Methods: This study was designed as a hospital-based retrospective observational case-series study. A total of 141 patients with metastatic EGFR mutant non-small cell lung cancer who has followed in two different oncology centers at Turkey between 2014 and 2020. have been included to this study. Results: The median age of the patients was 63 (range 35-91) years. EGFR mutation results of exon 19 deletion, exon 21 mutation and exon 18 mutation were found in 82 (58.2%), 56 (39.7%) and 3 (2.1%) patients, respectively. The median follow-up time was 22 months and 94 (33.3%) patients died during follow-up. Median overall survival (OS) was 26 months and progression free survival (for first line treatment) (PFS) was 10 months for whole patients, respectively. Radiotherapy was given to the primary tumor site in 32 (22,6%) patients. Patients receiving radiotherapy to primary tumor site had better overall survival than those not (31 versus 23 months respectively and p = 0,02) The survival advantage was also seen for patients group taking TKI at upfront setting (33 versus 23 months respectively and p = 0.05). Conclusions: In this study, we have showed that upfront thoracic radiotherapy to primary lession as combination with EGFR-TKI treatment may improve the outcome in advanced stage IV NSCLC patients harboring EGFR mutations.

Atezolizumab in first-line treatment of metastatic nonsquamous non-small cell lung cancer in the real-world setting.

e21112 Background: The phase III IMpower150 study showed efficacy benefits with atezolizumab in combination with bevacizumab, carboplatin and paclitaxel (ABCP; arm B) as first-line (1L) treatment for patients (pts) with metastatic non-squamous (nsq) NSCLC. The FDA approved this regimen for these pts (with no EGFR or ALK mutations [WT]) on December 2018. However, to date there is limited evidence on its use in real life. This study aimed to explore the use of ABCP in the real-world setting and to describe the characteristics of early adopters (those who received ABCP in 1L). Methods: Data were extracted from the Flatiron Health database (US population). Pts with advanced stage IIIB/IV nsq NSCLC at diagnosis receiving ABCP regimen in any line were eligible for the study. Finally, early adopters were selected. Results: A total of 67 pts received the ABCP regimen in 1L. Baseline characteristics for these pts and comparisons with the IMpower150 population are summarized in Table. Real-world (rw) response in the WT group ( n = 49; 6 pts were excluded due to EGFR mutations and 12 because minimum follow-up was not reached) was similar to that of the IMpower150 series (rwRR: 55.1% [40.2-69.3] vs. 63.5% [58.2-68.5]), despite the WT population being older with a higher proportion of ECOG PS = 1. In patients who would have met the IMpower150 inclusion criteria ( n = 24), rwRR was 70.8% (48.9-87.4). Conclusions: The ABCP regimen has been adopted in the real-world setting. In terms of efficacy, response rates and current PFS data were in line with trial results, despite the population being unselected and having a worse clinical profile. Longer follow-up is required for rwOS data. vs. arm B IMpower150 results.[Table: see text]

Does concurrent COX inhibition and immune checkpoint blockade improve clinical outcome in patients with metastatic renal cell carcinoma?

e16558 Background: Cyclooxygenase (COX) inhibition is postulated to restore the immune environment and synergizes with immune checkpoint inhibitors (ICI). The concurrent use of COX inhibitors (COXi) and ICI was associated with longer disease control in metastatic melanoma and non-small cell lung cancer. However, its role in mRCC remains unclear. Methods: We retrospectively reviewed 194 patients with mRCC treated with ICI (PD-(L)1 inhibitors +/- CTLA-4 inhibitors or TKIs) at Moffitt Cancer Center between 6/2014-7/2019. Concurrent use of COXi (aspirin [ASA] or NSAIDs) was defined as at least 3 weeks of COXi use during the first ICI course. Clinical characteristics of both arms were compared using Chi-squared or Kruskal-Wallis Rank Sum test. Time to progression (TTP) and Overall survival (OS) were compared using Kaplan Meier’s estimates. Univariate and multivariate Cox proportional hazards model was performed to evaluate the association between clinical factors, TTP, and OS. Results: Of 194 patients, 126 patients (64.9%) took COXi. Median age was 59.7 years and 80.4% were male. COXi arm had fewer patients with &lt; 1 year from diagnosis to systemic treatment (45.9% vs 69.5%, p = 0.006) and more advanced age (median: 66 years vs 60 years, p = 0.01). IDMC risk group, number of prior therapies, neutrophil to lymphocytes ratio were similar between both arms. Median TTP was 8 months (m) for COXi arm and 12m for ICI only (HR 1.38; 95% CI [0.98, 1.94]). Median OS was 27m for COXi arm and 33m for ICI only (HR 1.05, 95% CI [0.69, 1.59]). Early mortality rate (within 3m of ICI treatments) were similar between both arms. Conclusions: In contrast to melanoma and lung cancer, concurrent use of COXi and ICI did not improve TTP and OS in patients with mRCC. The dual blockade showed a trend for shorter TTP. Further validation studies with larger cohorts are needed to confirm this finding.[Table: see text]