Unresectable NSCLC Research Articles

EP.08F.14 Outcomes of Durvalumab Consolidation Treatment in Stage III Unresectable NSCLC: A Retrospective Real-World Study

EP.08F.14 Outcomes of Durvalumab Consolidation Treatment in Stage III Unresectable NSCLC: A Retrospective Real-World Study

1240MO Quantitative radiomics for the detection of symptomatic pneumonitis following chemoradiotherapy in patients with stage III unresectable NSCLC

1240MO Quantitative radiomics for the detection of symptomatic pneumonitis following chemoradiotherapy in patients with stage III unresectable NSCLC

Clinical prognostic factors for the effectiveness of immunotherapy in patients with unresectable NSCLC

: based on the univariate Cox regression model, six clinical characteristics showed a statistically significant effect on overall survival: sex, lymph node involvement, use of chemotherapy in the first line of treatment, low neutrophil count and neutrophil/lymphocyte ratio in the peripheral blood sample, which formed the basis for the formation of prognostic groups. This retrospective analysis of the first-line efficacy of patients with unresectable or metastatic NSCLC showed that the poor prognosis group may have a lower OS benefit with the addition of immunotherapy (9.4 months vs 9.8 months, p=0.256), compared with group with a favorable prognosis (19.9 months vs 23.6 months, p=0.045). Conclusions: definition of prognostic groups can be one of significant factors that could influence necessity of checkpoint inhibitors therapy. Researching of different therapy options efficacy in prognostic groups can lead to more precision usage of novel drugs. Keywords: immune checkpoint inhibitors, NSCLC, clinical prognostic factors.

Validation of the 10-gene expression profile for prediction of response to checkpoint inhibitor in patients with advanced NSCLS

Purpose: individualization of the use of immune checkpoint inhibitors in patients with inoperable NSCLC potentially sensitive to immunotherapy based on the level of the combined expression index as a predictive marker of effectiveness.Methods: in 146 patients with inoperable NSCLC, the level of the combined expression index in a tumor tissue sample was determined using PCR, which included studies of ten genes (CCL5, CXCL9, CXCR6, HLA-DQA1, TIGIT, EOMES, CTLA4, PD-L2, GZMB, PRF1). The patients were divided into cohorts depending on the level of the combined expression index and randomized into chemotherapy or immunotherapy groups. The null hypothesis of the study was that the group with a low combined expression index would have a 6-month progression-free survival of 35%, and with a high combined expression index – 75%, with α-error probability of 0.05, a power of 90%. Results: the use immune checkpoint inhibitors in the first line of the therapy for patients with a high level of the combined expression index leads to a significant increase in the rate of objective responses from 18% to 43%, the median overall survival from 10 to 21 months, and the median time to progression from 7.3 to 14.8 months. The 6-month progression-free survival rate in the group with a high combined expression index was 79%, versus 35% in the group with a low combined expression index. Conclusion: analysis of the gene expression signature can become one of the reliable predictive markers that predict the real effectiveness of therapy with immune checkpoint inhibitors, which will improve the results of treatment of patients with unresectable or metastatic NSCLC. Key words: NSCLC, immune checkpoint inhibitors, gene expression signature, predictive markers

Linking an early access program (EAP) to the National Health Data System (NHDS) in France and assessing its performances and potential biases.

11137 Background: Early access programs (EAP) are a unique opportunity to document first use of innovative treatments in real-world settings. The French HTA body requires mandatory patients’ clinical data collection for EAP and since July 2021, has recommended anticipating linkage EAP to the National Health Data System (NHDS). Prior to drug initiation, the collected data is almost complete contrary to follow-up data. To the best of our knowledge, no other study has proposed a methodology to link EAP to the French Cancer cohort (FCC), an extract of the NHDS of over 8 million persons diagnosed or at high risk of cancer, and to assess its assets and downsides. Methods: This cohort study has reused data of informed French EAP patients treated with durvalumab from October 1st, 2017 to December 31st, 2018 (n=457) in locally advanced unresectable NSCLC and of patients who received durvalumab at the time of the EAP in the FCC (n=666). The linkage methodology consists in harmonizing available data across sources, defining matching, control and study variables, testing several indirect deterministic linkage algorithms and assessing their performances. Consistency and differences between data sources were described for the best performing algorithm. Results: Proposed linkage algorithms required matches on a combination of data among sex, birth year and month, treating hospital ID and department. Performance started at 80.9% (370/457) patients from the EAP cohort linked to eligible patients from FCC up to 85.3% (390/457) for the best performing algorithm. The consistency of linkage variables between the two sources was substantial (Cohen’s kappa > 0.8) or excellent (intraclass correlation > 0.9). It was the same for control variables. Comparisons between linked patients and unlinked patients from the EAP cohort showed no statistically significant difference on matching and control variables, except for few cases on history of chemotherapy and history of radiation therapy prior to durvalumab. Similarly, no statistically significant difference was found on matching and control variables between linked patients and unlinked patients from FCC, except for history of radiation therapy and treating hospital department. Median of time difference between foreseen date of first durvalumab administration in EAP versus the effective date in FCC was -1 (IQR = [-9 ; 0]) day. Lack of reported diagnosis related to prior radiation therapy administration in out-of-hospital settings refrained from using them as matching or control variables. Conclusions: The study illustrates the feasibility of matching EAP patients to the French NDHS with indirect deterministic linkage. Additional EAP linkages will be required to ensure the validation and reproducibility of such methodology. Further works in progress will document the adequacy of French NHDS data to address effectiveness.

Relationship between immune phenotype and treatment selection of Chemo-IO vs. IO-only in TPS-high NSCLC using hypothetical test-and-control group generation based on survival data extracted from phase III trials.

e13569 Background: Immunotherapy has become the treatment of choice for the first-line treatment of unresectable NSCLC with high PD-L1 tumor proportion score (TPS). However, the optimal treatment regimen, particularly when to add chemotherapy, remains unclear. To evaluate whether an immune microenvironment biomarker could help guide the treatment regimen, we have explored computational hypothetical analysis applying historical proportion of inflamed immune phenotype (IIP) to published outcome data of clinical trials. Methods: R package “IPDfromKM” was used to reconstruct raw time-to-event outcomes from Kaplan-Meier (KM) curves. Data from KN-189 and KN-407 for anti-PD1 with chemotherapy (Chemo-IO), and KN-024 and KN-042 for anti-PD1 (IO-only) in the first-line treatment of NSCLC were included for analysis. Overall survival (OS) data were computed from KM of pts with PD-L1 TPS of ≧ 50% from these studies (KN-189 n=132, KN-407 n=73, KN-024 n=154, KN-042 n=299). It was assumed that Lunit SCOPE IO classified pts into IIP or non-IIP at a ratio of 57% vs. 43%, based on previous analysis. One hundred hypothetical sets of Chemo-IO and IO-only groups satisfying hazard ratio (HR) of IIP to non-IIP as 0.81 and 0.61 (± 0.025) while maintaining the proportion of IIP were randomly generated. A total of 10,000 (100 x 100) combinations of cohorts were analyzed to test our hypothesis of superiority of Chemo-IO over IO-only in non-IIP as well as non-superiority of Chemo-IO over IO-only in IIP. Results: Patient-level OS data for a total of 205 pts with Chemo-IO and 453 pts with IO-only were reconstructed. The median OS was favorable in Chemo-IO vs IO-only (HR 0.73, 95% confidence interval [CI] 0.54-0.99, p = 0.045). From 10,000 hypothetical combinations of cohorts, the median HR of Chemo-IO compared to IO-only was 0.61 (interquartile range [IQR] 0.60-0.63) in non-IIP group, whereas that was 0.86 (IQR 0.84-0.89) in IIP group (Table). The upper 95% bound of HR was < 1 for 8,611 combinations of non-IIP groups, but > 1 for all possible combinations of IIP groups. Given a non-superiority margin of 1.37(=1/0.73), 8,306 combinations were positive for the upper 95% bound of HR < 1.37. Overall, 6,917 matched combinations supported our hypothesis. Conclusions: From the computational analysis, 69.17% cases of hypothetical combinations support that Chemo-IO would be superior to IO-only in non-IIP group, whereas Chemo-IO would not be superior to IO-only in IIP group, implying a potential value of confirmatory biomarker analysis in providing evidence for regimen selection. [Table: see text]

Treatment outcomes in locally advanced, unresectable NSCLC treated with concurrent chemoradiation and PD-L1 consolidation: Real-world data from a NCI comprehensive cancer center with a racially diverse, high poverty catchment area.

Treatment outcomes in locally advanced, unresectable NSCLC treated with concurrent chemoradiation and PD-L1 consolidation: Real-world data from a NCI comprehensive cancer center with a racially diverse, high poverty catchment area.

An interpretable AI-derived radiology signature to identify patients at risk of progression on the PACIFIC regimen for unresectable non-small cell lung cancer.

8079 Background: Advances in the treatment of unresectable NSCLC have emerged through the combination of chemotherapy, radiotherapy, and immune checkpoint inhibitors (ICI), also known as the PACIFIC regimen. Despite this protocol’s benefits, it lacks predictive biomarkers and many patients will ultimately fail to respond. Artificial intelligence (AI) has shown promise in identifying patients responsive to ICI, but its ability to identify patients who may not benefit from such combination regimens remains underexplored. We introduce an AI-enabled approach leveraging interpretable imaging biomarkers, such as tumor heterogeneity and twistedness of the tumor-associated vasculature, to identify patients who will fail to benefit from chemo-radio-immunotherapy (CRIT) using pretreatment scans. Methods: We analyzed CT data from 148 NSCLC patients with predominantly stage III (91%) disease from two institutions. Target lesions were delineated by a trained radiologist. The Picture Health Px platform was utilized to segment the lungs and pulmonary vessels. Subsequently, a number of interpretable imaging features from the tumor and surrounding tissues were extracted. A Cox proportional hazards model of feature clusters was developed on the training set (n = 101) to stratify patients into benefit groups associated with progression-free survival (PFS). A cohort of 47 patients receiving CRIT were held out for testing. Results: The imaging-derived high-risk group defined by the model was associated with decreased PFS in the test set, with a hazard ratio (HR) of 4.99 (95% CI: 2.04-12.18; p < 0.005) and concordance index (C-index) of 0.66. The risk groups identified by the model outperformed PD-L1 negative status in identifying likely progressors (C-index = 0.52; HR = 1.49 [0.51-4.54], p = 0.47), and were additionally independently prognostic of PD-L1 status when compared in a multivariable analysis (p < 0.001). The primary features driving the model were measurements of the radius and tortuosity of the tumor-associated vasculature, as well as heterogeneity metrics of the tumor. Conclusions: An AI imaging tool that stratifies patients by risk after CRIT from baseline radiology was developed. The tool was able to strongly identify a subset of patients at very high risk of progression if treated with CRIT. These risk groups outperformed PD-L1 and thus may address biomarker gaps in the CRIT setting. With further clinical validation, radiology-based risk stratification could be used to identify a subset of unresectable NSCLC patients for whom alternatives to the standard of care should be explored.

Abstract 7617: Quantitative continuous scoring of PD-L1 for superior patient selection for anti-PD-L1 treatment of locally advanced or unresectable NSCLC

Abstract Background: Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 following concurrent chemoradiotherapy (cCRT) have shown clinical activity in locally advanced, unresectable NSCLC, e.g. with the PACIFIC regimen [1]. PD-L1 expression is typically assessed by pathologist scoring of immunohistochemically (IHC) stained tissue using the tumor cell (TC) score. In this work, we present PD-L1 Quantitative Continuous Scoring (PD-L1 QCS) to digitally assess PD-L1 expression (Ventana SP263 assay), and analyze its utility for identification of patient subgroups with higher likelihood of treatment response. Method: 368 digitized whole slide images (WSI) of fresh biopsy and archival samples were obtained from the PACIFIC trial (NCT02125461), including 126 patients who received placebo and 242 patients who received Durvalumab post-cCRT [1]. WSI analysis included two deep learning models for epithelial TC segmentation followed by optical density (OD) quantification of membrane expression [2]. Initially, PD-L1 QCS was calibrated to compute the TC score at 1% cutoff by determining an optimal OD cell positivity threshold. Next, other scoring approaches were investigated, which included various OD thresholds and biomarker cutoffs. Results: PD-L1 QCS-based TC scoring was able to maintain median overall survival (mOS) of 57.4 months in the biomarker positive (BM+) ICI cohort, while increasing prevalence to 191 out of 242 patients (78.9%) compared to 177 (73.1%) with manual TC score at 1% cutoff. Extending the scoring paradigm to the PD-L1+ TC density >= 542.5 cells/mm² lead to a more pronounced increase of prevalence to 200 patients (82.6%) in the ICI population, while mOS was not reached and additionally showed comparable hazard ratios (HR) when evaluating against the BM+ placebo cohort (HR=0.54 [0.39, 0.76] resp. HR=0.52 [0.37, 0.74]). Results further demonstrated that PD-L1 QCS density scoring of the ICI treated population allowed for a clearer separation of patients with less treatment benefit (34.2m mOS, N=42, log rank p=0.0067) compared to manual scoring (47.4m mOS, N=65, log rank p=0.2). Conclusion: We investigated a computational pathology approach for selecting patients for treatment with the PACIFIC regimen and compared it against established manual pathology scoring. Results indicate that PD-L1 QCS TC proportion scoring can increase prevalence, while PD-L1 QCS TC density scoring has the potential to identify an even larger patient subgroup with increased survival benefit.

Plunging Into the PACIFIC: Outcomes of Patients With Unresectable KRAS-Mutated Non-Small Cell Lung Cancer Following Definitive Chemoradiation and Durvalumab Consolidation

BackgroundImmune checkpoint inhibitor (ICI) consolidation following concurrent chemoradiotherapy (CRT) substantially improved progression free survival (PFS) and overall survival (OS) in the PACIFIC trial becoming the standard of care in locally-advanced, unresectable NSCLC. KRAS mutation may influence response to ICI. MethodsIn this single-institution, retrospective analysis, we compared treatment outcomes for patients with unresectable KRAS mutated (KRAS-mt) and wild-type (KRAS-wt) NSCLC treated with CRT between October 2017 and December 2021. Kaplan–Meier analysis was conducted comparing median progression free survival and median overall survival from completion of radiotherapy in all KRAS-mt patients and KRAS-G12C-mutated patients. Outcomes were also compared with and without ICI consolidation. ResultsOf 156 patients, 42 (26.9%) were KRAS-mt and 114 (73.1%) were KRAS-wt. Baseline characteristics differed only in histology; KRAS-mt NSCLC more likely to be adenocarcinoma. KRAS-mt patients had worse PFS (median 6.3 vs. 10.7 months, P = .041) but similar OS (median 23.1 vs. 27.3 months, P = .237). KRAS-mt patients were more likely to not receive ICI due to rapid disease progression post-CRT (23.8% vs. 4.4%, P = .007). Among patients who received ICI (n = 114), KRAS-mt was not associated with inferior PFS (8.1 vs. 11.9 months, P = .355) or OS (30.5 vs. 31.7 months, P = .692). KRAS-G12C patients (n = 22) had similar PFS and OS to other KRAS-mt. ConclusionIn one of the largest post-CRT KRAS-mt cohort published, KRAS-mt was associated with inferior PFS, largely due to rapid progression prior to ICI consolidation, but did not affect OS. Among those who received ICI consolidation, outcomes were comparable regardless of KRAS-mt status.

Bintrafusp Alfa With CCRT Followed by Bintrafusp Alfa Versus Placebo With CCRT Followed by Durvalumab in Patients With Unresectable Stage III NSCLC: A Phase 2 Randomized Study

IntroductionPreclinical evaluation of bintrafusp alfa (BA) combined with radiotherapy revealed greater antitumor effects than BA or radiotherapy alone. In a phase 1 study, BA exhibited encouraging clinical activity in patients with stage IIIB or IV NSCLC who had received previous treatment. MethodsThis multicenter, double-blind, controlled phase 2 study (NCT03840902) evaluated the safety and efficacy of BA with concurrent chemoradiotherapy (cCRT) followed by BA (BA group) versus placebo with cCRT followed by durvalumab (durvalumab group) in patients with unresectable stage III NSCLC. The primary end point was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by the investigator. On the basis of the recommendation of an independent data monitoring committee, the study was discontinued before the maturity of overall survival data (secondary end point). ResultsA total of 153 patients were randomized to either BA (n = 75) or durvalumab groups (n = 78). The median progression-free survival was 12.8 months versus 14.6 months (stratified hazard ratio = 1.48 [95% confidence interval: 0.69–3.17]), in the BA and durvalumab groups, respectively. Trends for overall response rate (29.3% versus 32.1%) and disease control rate (66.7% versus 70.5%) were similar between the two groups. Any-grade treatment-emergent adverse events occurred in 94.6% versus 96.1% of patients in the BA versus durvalumab groups, respectively. Bleeding events in the BA group were mostly grade 1 (21.6%) or 2 (9.5%). ConclusionsBA with cCRT followed by BA exhibited no efficacy benefit over placebo with cCRT followed by durvalumab in patients with stage III unresectable NSCLC.

Prospective Phase II Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy (SBRT) Followed By Concurrent Mediastinal Chemoradiation and Adjuvant Immunotherapy for Locally-Advanced Non-Small Cell Lung Cancer (LA NSCLC)

To report the efficacy and toxicity outcomes of a prospective phase II trial of primary tumor SBRT followed by conventional chemoradiation to the lymph nodes and adjuvant immunotherapy in patients (pts) with unresectable LA NSCLC. Eligible pts included stage II-III LA NSCLC with peripheral primary tumors ≤ 7cm or centrally based tumors that had at least 2 cm separation from involved nodal disease. Pts received SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by standard radiation to 60 Gy in 30 fractions to the involved lymph nodes with concurrent platinum doublet chemotherapy. The trial was amended to allow pts without disease progression after chemoradiation to receive adjuvant durvalumab per the PACIFIC trial. The primary endpoint was 1 year progression free survival (PFS), evaluated as a binary variable. Frequencies and proportions were used for reporting this primary endpoint, in addition to adverse events and patterns of failure. Median PFS and OS were estimated using Kaplan Meier methods. Safety and efficacy is reported on the first 50 pts enrolled in the trial with a median follow-up of 24 months (mos) (range, 1-54 mos). Pts were primarily stage IIIA (60%) or stage IIIB (34%), with 6% of pts stage IIB. Overall grade 3 or higher toxicity related to SBRT and/or mediastinal radiation was 8% with two pts (4%) developing grade 3 pneumonitis and one pt having a grade 5 lung infection possibly related to radiation. Overall grade 2 pneumonitis related to SBRT or mediastinal radiation was 20%. Only one pt (2%) developed grade 3 esophagitis. No late cardiac events have been observed. The one-year PFS for all pts was 62% with a median PFS of 26.3 mos and median overall survival of 40.8 mos. Of the 50 pts enrolled, 37 received at least one dose of adjuvant durvalumab. The one-year PFS for pts who received at least one dose of durvalumab was 70.3% with a median PFS not yet reached in this group (median follow-up 24 mos). Patterns of failure were mostly distant with 26% of pts experiencing distant failure, 6% regional, and 2% distant and regional. There was only one local failure (2%) after SBRT in all 50 pts. SBRT to the primary tumor followed by conventional chemoradiation to the involved lymph nodes and adjuvant immunotherapy was well tolerated and showed improved 1-year PFS compared to prior conventional chemoradiation trials for locally advanced NSCLC. The results of this trial will be further evaluated in a randomized phase III study, NRG LU-008. Pts will receive either conventional chemoradiation vs. SBRT to the primary tumor followed by chemoradiation to the involved lymph nodes followed by consolidative immunotherapy to evaluate the possibility of utilization of SBRT as a new standard of care for LA NSCLC.

Residual ctDNA Detection Predicts Benefit From Definitive Chemoradiotherapy and Immune Checkpoint Inhibitors in Locally Advanced NSCLC

Therapeutic efficacy differs across unresectable locally advanced non-small cell lung cancer (LA-NSCLC) patients receiving definitive chemoradiotherapy (CRT), and the dynamic change in circulating tumor DNA (ctDNA) is closely associated with clinical outcomes. However, evidence for the predictive effect of ctDNA in LA-NSCLC patients with CRT and immunotherapy, the current standard of care, remains limited. It is unclear whether residual ctDNA after definitive CRT can guide clinical decisions on further use of immune checkpoint inhibitors (ICIs) consolidation. We prospectively included 73 patients with unresectable stage II-III NSCLC. All patients received definitive concurrent or sequential CRT, with the prescribed dose of 60 Gy and ≥2 cycles of platinum-based chemotherapy. Thirty-seven (50.7%) patients further underwent ICIs therapy (18 durvalumab, 9 pembrolizumab, 10 others). Peripheral blood samples were collected from all patients before any treatment (baseline), 1 month after CRT (post-CRT), and at the time of progression. All plasma specimens were analyzed with next-generation sequencing panel of 474 cancer-related genes. Plasma samples with ≥1 variant detected were defined as detectable ctDNA. The primary endpoint was progression-free survival (PFS). After the median follow-up of 25.4 months, median overall survival (OS) was not reached (NR), and median PFS was 16.7 months (95% CI, 12.4-26.6) for all patients. Compared with baseline, ctDNA abundance significantly decreased after definitive CRT (P<0.001) but relatively increased at progression (P = 0.051). Patients treated with CRT plus ICIs exhibited significantly longer OS (median, NR vs 22.1 months [95% CI, 16.7-NR]; P = 0.002) and PFS (median, 24.8 months [95% CI, 16.1-NR] vs 11.4 months [95% CI, 6.5-NR]; P = 0.016) than those with CRT alone. Post-CRT residual ctDNA was associated with significantly poorer OS (median, 18.3 months [95% CI, 14.8-NR] vs NR; P = 0.002) and PFS (median, 6.5 months [95% CI, 5.6-NR] vs 24.8 months [95% CI, 18.8-NR]; P<0.001), whereas baseline ctDNA predicted neither OS (P = 0.310) nor PFS (P = 0.570). For patients with post-CRT detectable ctDNA, further ICIs therapy brought significant benefit in both OS (median, NR vs 14.8 months [95% CI, 12.0-NR]; P = 0.012) and PFS (median, 16.1 months [95% CI, 5.8-NR] vs 6.2 months [95% CI, 4.2-NR]; P = 0.043). However, in patients with post-CRT ctDNA clearance, there was no significant difference in OS (P = 0.080) or PFS (P = 0.151) between patient with and without ICIs, which suggested less clinical benefit. Post-CRT residual ctDNA predicted worse survival in LA-NSCLC, but indicated more benefit from further ICIs therapy and thereby could facilitate personalization of consolidation immunotherapy. Further prospected studies with large sample size are warranted to validated these findings.

Efficacy and surgical safety of sequential surgical resection after pembrolizumab plus chemotherapy for initial unresectable stage IIIB non-small cell lung cancer

IntroductionNeoadjuvant immunochemotherapy is effective in resectable NSCLC. However, its role in unresectable stage IIIB NSCLC patients remains controversial. This study aimed to demonstrate the efficacy and safety of neoadjuvant immunochemotherapy followed by surgical resection to treat initial unresectable stage IIIB NSCLC patients. MethodsThis study retrospectively analyzed 59 initial unresectable stage IIIB NSCLC patients who received induction pembrolizumab combined with chemotherapy between June 2019 and April 2022. Clinical characteristics, radiological and pathological responses, and survival outcomes were collected and evaluated. ResultsFifity-nine initial unresectable stage IIIB NSCLC patients were identified and divided into surgery (n = 23) and non-surgery (n = 36) groups with a median follow-up time of 15.0 months. The median PFS/DFS of the surgery group was significantly longer than the non-surgery group (not reached vs. 15.5 months, p = 0.0031). The median overall survival (OS) was not reached in both groups, and the OS rate was 100% (23/23) in the surgery group and 83.3% (30/36) in the non-surgery group. The pathological analysis suggested that 13 of 23 patients (56.5%) achieved major pathological response (MPR) or pathological complete response (pCR), and more squamous cell carcinoma cases were observed in the MPR group compared to the non-MPR group (p = 0.034). All patients in the surgery group had an R0 resection, and no surgical-related mortality was recorded; only three patients (13.0%) experienced any postoperative complications. ConclusionIn this retrospective study, surgical resection after neoadjuvant immunochemotherapy was promising for initial unresectable stage IIIB NSCLC patients, with a high MPR rate and good surgical safety.

Identifying correlates of post treatment responses for unresectable locally advanced non-small cell lung cancer (LA NSCLC).

149 Background: Curative treatment for unresectable LA NSCLC comprises chemoradiotherapy (CRT) and immunotherapy (IO). However, this uniform approach does not take into account the intrinsic heterogeneity of NSCLC and nearly half of all pts relapse within the first year. This highlights the need to define distinct molecular and phenotypic subgroups of LA NSCLC so that we can interrogate the divergent responses to CRT-IO and identify biomarkers that can guide pt specific strategies. Methods: Consecutive pts treated with CRT +/- IO from May 2010 and recruited to an observational study were retrospectively analysed (N = 336). All pts with adenocarcinoma (ADC) were subject to reflex molecular profiling including NGS and FISH testing for ALK, ROS1, MET and RET. Of note, tracking of bespoke circulating tumour DNA (ctDNA) levels was performed for 25 pts. Plasma samples were collected at longitudinal timepoints pre, during and post CRT (N = 118; median 5 samples/ pt). WES of biopsies and matched normal DNA was used to design tumour informed ctDNA assays to track 16 single nucleotide variants in plasma samples. ctDNA levels were then quantified as mean tumour molecule per mL (MTM/mL). Primary endpoint was progression free survival (PFS). Results: Median age was 61 (IQR 48, 74). Of 336 pts, 74% were male; 32% never smokers; 54% were ADC, 33% squamous cell carcinoma (SCC); 18% had EGFR mutations (EGFRm), 37%EGFR wild type (EGFRw), 40% unknown EGFR status (EGFRu), 5% ALK rearranged, 1% ROS1 rearranged. At median follow-up of 44 months (m), median PFS for the entire cohort was 16.2m. Pts who received consolidation IO had longer PFS [IO, not reached vs no IO, 14.9m; P = 0.05]. Median PFS was shorter for pts with EGFRm [EGFRm, 13m vs EGFRw, 22.5m vs EGFRu, 15.8m]. Patterns of failure were analysed according to local in-field, regional out-field and distant. EGFRm pts were less likely to fail locally in-field [EGFRm, 12% vs EGFRw,18% vs EGFRu, 28%] and significantly more likely to develop distant metastases as first site of failure post CRT [EGFRm, 51% vs EGFRw, 28% vs EGFRu, 19%; P = 0.01]. For the 25 pts with ctDNA analysed, 24 pts had evaluable ctDNA post CRT. Significant heterogeneity was noted at baseline pre CRT [EGFRm, 6.45 vs EGFRw, 7.49 vs SCC, 37.67 MTM/mL; P = 0.05]. No difference was noted in PFS between pts with high vs low baseline ctDNA. Of note, 14 of 24 (58%) pts achieved undetectable ctDNA post CRT and had significantly longer PFS [undetectable, 24.1m vs detectable, 3.5m; P = 0.02]. Conclusions: Here, we demonstrate distinct phenotypic responses to CRT based on molecular subtypes of NSCLC. Crucially, we demonstrate clinical feasibility of deploying tumour-informed ctDNA assays in LA NSCLC with detection of ctDNA post CRT serving as a potential actionable biomarker to guide intensification strategies, providing a window into developing patient-specific combinatorial approaches.

Lung adenocarcinoma and squamous cell carcinoma difficult for immunohistochemical diagnosis can be distinguished by lipid profile

In patients with unresectable non-small cell lung cancer, histological diagnosis is frequently based on small biopsy specimens unsuitable for histological diagnosis when they are severely crushed and do not retain their morphology. Therefore, establishing a novel diagnostic method independent of tissue morphology or conventional immunohistochemistry (IHC) markers is required. We analyzed the lipid profiles of resected primary lung adenocarcinoma (ADC) and squamous cell carcinoma (SQCC) specimens using liquid chromatography-tandem mass spectrometry. The specimens of 26 ADC and 18 SQCC cases were evenly assigned to the discovery and validation cohorts. Non-target screening on the discovery cohort identified 96 and 13 lipid peaks abundant in ADC and SQCC, respectively. Among these 109 lipid peaks, six and six lipid peaks in ADC and SQCC showed reproducibility in target screening on the validation cohort. Finally, we selected three and four positive lipid markers for ADC and SQCC, demonstrating high discrimination abilities. In cases difficult to diagnose by IHC staining, [cardiolipin(18:2_18:2_18:2_18:2)-H]− and [triglyceride(18:1_17:1_18:1) + NH4]+ showed the excellent diagnostic ability for ADC (sensitivity: 1.00, specificity: 0.89, accuracy: 0.93) and SQCC (sensitivity: 0.89, specificity: 0.83, accuracy: 0.87), respectively. These novel candidate lipid markers may contribute to a more accurate diagnosis and subsequent treatment strategy for unresectable NSCLC.

Efficacy and safety of pembrolizumab plus chemotherapy and sequential surgical resection in initial unresectable stage IIIB NSCLC.

e20595 Background: Neoadjuvant immunochemotherapy has been proved effective in resectable NSCLC, while its role in unresectable stage IIIB NSCLC remains controversial. This study aims to demonstrate the efficacy and safety of neoadjuvant immunochemotherapy sequential surgical resection in initial unresectable stage IIIB NSCLC patients. Methods: This multicenter study retrospectively analyzed 59 patients with initial unresectable stage IIIB NSCLC who received induction pembrolizumab combined with chemotherapy between June 2019 and April 2022. The clinical characteristics, radiological and pathological response and survival outcomes were collected and evaluated. Results: A total of 59 initial unresectable stage IIIB NSCLC patients were identified and divided into the surgery group (n = 23) and non-surgery group (n = 36) with a median follow-up time of 15.0 months. The median PFS/DFS of surgery group was significantly longer than that of non-surgery group (not reached versus 15.5 months, p = 0.0031). The median OS was not reached in both groups, overall survival rate was 100% (23/23) in surgery group and 83.3% (30/36) in non-surgery group. Pathological analysis suggested that 13 of 23 patients (56.5%) achieved major pathological response (MPR) or pathological complete response (pCR), and more squamous cell carcinoma cases were observed in MPR group compared to non-MPR group ( p = 0.034). Of 23 patients in surgery group, all patients had a R0 resection, no surgical-related mortality was recorded, only 3 patients (13.0%) experienced any postoperative complications. Conclusions: Surgical resection after neoadjuvant immunochemotherapy is beneficial in the survival outcome of initial unresectable stage IIIB NSCLC patients, with a high MPR rate and good surgical safety.

Patients’ epidemiology in stage III, unresectable non-small-cell lung carcinoma: A real-world analysis in Brazil.

e20589 Background: Although breakthrough therapy options for NSCLC have emerged in the last few years, lung cancer is still the principal cause of cancer-related deaths in both men and women worldwide. In Brazil, lung cancer is the major cause of cancer mortality – the second most common cause of cancer-related death in females and the first cause among males. The main factors contributing to the high burden of the disease remain the late-stage diagnosis and unequal healthcare access, which are most prevalent in low- and middle-income countries. This study aimed to describe lung cancer epidemiology – patients in stage III, unresectable NSCLC that could benefit from consolidation therapy after chemoradiation (CRT) treatment - in the Brazilian public health system for evaluating the future impact of new therapies. Methods: We gathered information on lung cancer procedures performed between January 2018 and October 2022 using the Brazilian public health system database (DATASUS). Since this is a claim medical database without clinical data, assumptions were specified based on procedures performed to determine the potential number of patients in Brazil who would benefit from these new treatment strategies in stage III NSCLC. The assumptions were the following: 1. Having received systemic therapy for a malignant tumor of the bronchi and lung (ICD-10 - C34); 2. Having received a pre-defined list of chemotherapy regimens (to define which patients were NSCLC); 3. Having started systemic therapy with a Stage III tumor; 4. Having not undergone surgery between three months before and two months following the start of systemic treatment 5. Treated with chemotherapy and radiotherapy (concomitantly or sequentially - until two months later); 6. Patients who died or progressed during treatment were classified as incomplete treatment. Results: Between 2018 and 2022, we identified an average of 9,340 patients each year who started therapies for lung cancer; 75% (7,023) of them performed specific procedures for NSCLC and were classified as such. 21% (1,472) of patients started treatment for stage III NSCLC, and 98% (1,438) of these cases were unresectable. Of these, 26% (377) received chemotherapy and radiation, 92% of whom finished the course of treatment. In Brazil, 346 patients per year with stage III unresectable NSCLC could be treated with consolidation therapy after CRT in the public health system. Conclusions: The number of NSCLC patients who can benefit from consolidation therapy after CRT (346) represents 3.7% of all lung cancer patients starting systemic treatment annually. It allows a better management of the possible economic impact of the addition of this new therapy in the Brazilian health public system. Increased screening for early diagnosis and improving access to CRT would expand the patient population eligible for this therapeutic approach.

Management and treatment of patients with stage III unresected NSCLC at UPMC: A quality initiative by Integra Connect Precision Q.

e20588 Background: The PACIFIC trial led to improved OS in patients (pts) with unresectable stage 3 NSCLC who received durvalumab (durva) post chemoradiation (CRT).1 In 2019, the University of Pittsburgh Medical Center (UPMC) and IC initiated a QI to improve immunotherapy (IO) use post CRT. A baseline analysis was done to assess scanning and treatment patterns post-CRT, and duration of treatment (DOT) with durva. Drawing on this analysis, IC and UPMC conducted a focus group to address gaps in care and initiated improvements. This real-world study aims to assess the change in IO use post-CRT, the time to scan (TTS), time to treatment (TTT), and duration of treatment (DOT) compared to baseline. The DOT of durva was compared between pts initiated &lt;14 days of CRT and those who started ≥14 days. Methods: From the UPMC and IC Precision Q real-world databases, we identified 555 pts with stage 3 unresectable NSCLC for manual chart abstraction. Pts received CRT between 2/16/2018 and 12/31/2021. TTS was calculated from the last day of CRT to the 1st scan and the TTT obtained from the last day of CRT to the 1st durva dose. The baseline period was from 2/16/2018 to 8/31/2020 and the post-intervention stage from 9/1/2020 to 12/31/2021 based on CRT start date. Pts were excluded if they had no scan data, a 1st scan ≥90 days post CRT (TTS analyses), a duration of zero days (DOT analyses) or a TTT &gt;120 days (TTT analyses). At least 1 yr of follow up was required for DOT comparisons. Descriptive analyses were used. A two-tailed 2 sample z-test was used for proportions and the nonparametric Wilcoxon rank sum test was used for TTS, TTT and DOT comparisons. Results: The baseline pts were 46% female with an average age of 67.7 years and the post-intervention were 47% female with an average age of 69.4 years. The rate of durva use post CRT in pts who did not progress increased from 66% (n =128/194) at baseline to 83% (n =96/116) post intervention (p &lt; 0.01). The baseline median TTS decreased from 22.5 days (n=174) to 20 days (n=121) post intervention (p &lt;0.05), and median TTT decreased from 35 days (n=121) to 28 days (n=90) (p &lt; 0.05). The median DOT increased from 6 (n=127) to 8.2 months (n=76) (p &gt;0.05). During the study period, 8% (n =17/223) of pts started durva &lt; 14 days post CRT and 92% started ≥14 days (n =206/223). The median DOT in the &lt; 14 days group was 10.8 months versus 6.2 months in ≥14 days (p &gt;0.05). The median overall survival (OS) was 36.5 months in the &lt; 14 days vs. 27.8 months in the ≥14 days group (p &gt; 0.05). Conclusions: QIs in NSCLC are effective tools that can improve appropriate durva utilization, TTT and DOT in eligible pts. Practices that assess their clinical performance can identify gaps in care and act. In this study, a superior OS, though lacking statistical significance, was seen in the group that started IO &lt;14 days post CRT compared to ≥14 days. Further studies with larger sample size, are needed to validate these findings.

Surgical outcomes and patient-reported outcomes of unresectable stage III non-small cell lung cancer patients who underwent PD-1 inhibitor plus chemo as induction therapy.

e20570 Background: For locally advanced unresectable NSCLC, studies of PD-1 inhibitor plus chemo as induction therapy and its roles on subsequent surgical resection are still limited. In this study, a consecutive series of unresectable stage III NSCLC patients were collected to investigate the surgical outcome and postoperative symptom changes in locally advanced patients who received adjuvant chemotherapy combined with immunotherapy. Methods: 92 locally advanced NSCLC patients received 2-4 cycles of chemotherapy combined with immunotherapy. Surgical rates, major pathologic remissions(MPR), pathologic complete remissions(PCR), postoperative complications, and immune-related adverse reactions(irAEs) were assesd. The follow-up of symptoms was performed during treatment and within 3 months postoperatively, and symptom changes were described based on patient-reported outcomes. Results: 26.09% of patients developed irAEs, the most common was skin toxicity, followed by thyroid dysfunction. 71.74% of patients underwent surgical resection. 63.64% (42/66) achieved MPR and PCR, of which 37.87% (25/66) were PCR. Most of these patients have clinical symptoms at the time of presentation, mainly cough (90%), and after treatment, cough is significantly reduced compared with before treatment. After treatment, the cough was significantly reduced compared with before treatment , nausea and vomiting , loss of appetite , dry mouth , and diarrhea were increased or aggravated. The most common symptoms on the first day after operation included pain (90%), shortness of breath (62.5%), fatigue (45%), cough (42.5%), and dry mouth (37.5%). On the third day after surgery, the incidence and severity of each symptom changed significantly, pain and dry mouth decreased significantly compared with before, cough, shortness of breath, and fatigue worsened and the incidence increased. Pain remains the most severe symptom in the early postoperative period, with the most severe on the first day after operation and then reduced, returning to preoperative levels 1.5 months after surgery. Cough was the main symptom at the time of presentation, which was significantly reduced after preoperative treatment, and the incidence and severity of postoperative cough increased significantly compared with preoperative treatment and returned to the preoperative level within 1 week after surgery. Dyspnea lasts long after surgery. Two weeks after surgery, shortness of breath (dyspnea) becomes the most obvious symptom. Conclusions: Preoperative chemotherapy combined with immunotherapy provides more opportunities for radical resection in locally advanced NSCLC patients. The most common postoperative symptoms are pain, dyspnea, cough, and fatigue; dyspnea is the symptom that affects patients the most and lasts the longest after surgery.