IIIB Non-small Cell Lung Cancer Research Articles

Dosimetric comparison of four radiotherapy techniques for stage III non‑small cell lung cancer.

The present study was implemented to compare the dosimetric parameters of the target dose coverage and critical structures in the treatment planning of four radiotherapy techniques [namely, three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), hybrid IMRT (h-IMRT) and volumetric-modulated arc therapy (VMAT)] for stage III non-small cell lung cancer (NSCLC) qualified plans for medical physicists, therapists and physicians. A total of 40 patients confirmed to have stage IIIA or IIIB NSCLC were enrolled, and four plans were designed for each patient. The prescription dose to the planning target volume (PTV) was assigned as 60 Gy in 30 fractions. The conformity index (CI), heterogeneity index (HI) and parameters of organs at risk (OARs) were calculated. For the PTV, the CI for VMAT was found to be the highest of all the four techniques (P<0.05), whereas the HI for the h-IMRT technique was found to be the lowest (P<0.05). Concerning the OARs, for the percentage of lung volume receiving a dose >5 Gy (lung V5), the highest value was obtained with VMAT (P<0.05), whereas for lung V30 and heart V30, the VMAT and IMRT techniques were found to be better compared with 3D-CRT and h-IMRT (P<0.05). For esophagus V50, the maximal dose (Dmax) and mean dose for the IMRT technique displayed the best results (P<0.05), and in the case of the spinal cord, the Dmax with VMAT showed a significant advantage over the other techniques (P<0.05). The treatment monitor units (MUs) in IMRT were found to be the largest (P<0.05), whereas the treatment time with VMAT was the shortest (P<0.05). For smaller PTVs, VMAT was the technique that provided the optimal dose distribution and sparing of the heart. Compared with 3D-CRT alone, adding 20% IMRT to the 3D-CRT base plan was shown to improve the plan quality, and IMRT and VMAT, as techniques, had better dose coverage and sparing of OARs. Furthermore, for patients in whom the lung V5 could be kept low enough, VMAT potentially offered a good alternative to the technique to IMRT, thereby offering additional possibilities for sparing of other OARs, and decreasing the MUs and treatment time.

Updated Findings of the Phase II LCMC3 Trial of Lung Cancer Patients

Lung Cancer: Lung CancerResults from an exploratory analysis of the Phase II LCMC3 trial showed that patients with resectable Stage IB-IIIB non-small cell lung cancer (NSCLC) who received adjuvant atezolizumab following neoadjuvant atezolizumab and resection had improved disease-free survival compared with those who were not administered adjuvant atezolizumab. These findings, presented during the 2023 European Lung Cancer Congress, also demonstrated a trend toward improved overall survival among patients who underwent adjuvant atezolizumab (Abstract 145MO). “Neoadjuvant chemoimmunotherapy (IO) treatment without adjuvant treatment in CheckMate 816 has shown to improve pathologic responses and event-free survival outcomes,” noted study author David P. Carbone, MD, PhD, the Barbara J. Bonner Chair in Lung Cancer Research and Director of the James Thoracic Center at The James Ohio State University Comprehensive Cancer Center. “However, it is completely unclear what the role of adjuvant immunotherapy is after neoadjuvant immunotherapy and there is no current study testing the role of adjuvant IO.” LCMC3 (NCT02927301) is an open-label, single-arm, Phase II study of neoadjuvant followed by optional adjuvant atezolizumab (anti-PD-L1) in resectable NSCLC. The primary endpoint—major pathological response (MPR)—was met with an observed MPR rate of 20 percent after neoadjuvant atezolizumab in patients without EGFR or ALK alterations who underwent surgery (Nature Med 2022; doi: 10.1038/s41591-022-01962-5). Carbone and colleagues report updated disease-free survival, overall survival, and safety data from patients who received adjuvant atezolizumab versus those who did not. Methods & Findings Patients eligible for this study included those 18 years or older who had Stage IB-IIIA or select IIIB NSCLC, as well as an ECOG performance status of 0-1. The primary endpoint was major pathologic response (≤10% viable tumor cells). Secondary endpoints included pathologic response by PD-L1 and radiographic response by PD-L1, TMB, neoantigen, and GEP. Disease-free survival, overall survival, and biomarkers were exploratory endpoints. Safety was also examined during the adjuvant phase. Study participants received neoadjuvant atezolizumab (1,200 mg IV for ≤2 cycles) followed by surgery. Individuals without disease progression had the option to undergo adjuvant atezolizumab every 3 weeks for ≤12 months. With a data cutoff of October 21, 2022, the primary efficacy population included 137 patients without EGFR/ALK alterations who had surgery and MPR assessment. Of those, 53 (39%) received adjuvant atezolizumab and 84 (61%) did not. The baseline characteristics between these two groups were generally well-balanced, according to Carbone. However, he did note that patients who received adjuvant atezolizumab had a higher rate of squamous NSCLC (47% vs. 31%). They were also more likely to have a PD-L1 tumor proportion score (TPS) of 50 percent or higher (40% vs. 27%) and MPR status (42% vs. 8%) when compared to their counterparts who did not receive adjuvant atezolizumab. Study authors reported an updated 3-year disease-free survival and overall survival rate for the entire cohort of 72 percent and 82 percent, respectively. Disease-free and overall survival rates for Stage I/II were 75 percent and 82 percent, and 68 percent and 81 percent for Stage III. In the MPR-evaluable population, the 3-year disease-free survival rate was 83 percent for those who were given adjuvant atezolizumab versus 64 percent for those who did not receive this treatment. Among patients without MPR (n=108), Carbone reported a 3-year disease-free survival of 80 percent for individuals who underwent adjuvant atezolizumab compared with 62 percent for those who did not. Three-year overall survival was 87 percent and 75 percent, respectively. Carbone reported no unexpected safety findings. Among patients in the adjuvant atezolizumab safety population (n=57), any-grade adverse events (AEs) were observed in 96 percent of patients, including Grade 3/4 (40%) and Grade 5 (5%) adverse events. Treatment-related adverse events of any grade were reported in 63 percent of patients. Twenty-one percent had a Grade 3 treatment-related adverse event. Study authors reported that 23 percent of patients experienced any-grade AEs that led to treatment discontinuation, including 19 percent with Grade 3/4 (19%) and Grade 5 (2%) adverse events. Immune-mediated adverse events were seen in 46 percent of patients treated with adjuvant atezolizumab. This included 16 percent with a Grade 3/4 event. Study authors reported that 33 percent of patients experienced any-grade immune-mediated treatment-related adverse events with 16 percent being Grade 3/4. Significance & Implications This exploratory analysis suggests that LCMC3 patients with resectable NSCLC who received adjuvant atezolizumab may have improved disease-free survival and showed a trend toward improved overall survival when compared with those who did not receive adjuvant atezolizumab, according to Carbone. “The non-MPR subgroup also showed a trend toward improved disease-free survival and overall survival in patients who received adjuvant atezolizumab,” he said, while also emphasizing that adjuvant atezolizumab was well-tolerated with no new safety concerns. “This single-arm study showed that outcomes were better than anticipated in patients who received adjuvant atezolizumab, which may prompt further studies of IO monotherapy,” Carbone concluded. Catlin Nalley is a contributing writer.

Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer

BackgroundAmong patients with resectable early-stage non–small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone.MethodsWe conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety.ResultsA total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P=0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P=0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P=0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events.ConclusionsAmong patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.)

First-line immune checkpoint inhibitors alone or in combination with chemotherapy in real-life elderly patients with advanced non-small cell lung cancer (NEJ057).

9012 Background: Immune checkpoint inhibitor (ICI) plus chemotherapy is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alternations. However, the efficacy and safety of ICI plus chemotherapy (ICI-chemo) in 75 years or older patients have not been elucidated. The aim of this study is to reveal the real-world choice of first-line drugs in elderly patients (pts) and evaluate the efficacy and safety of ICI-chemo. Methods: We conducted a multicenter (58 centers in Japan), retrospective cohort study of consecutive 75 years or older pts with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC who started first-line systemic therapy between December 2018 and March 2021. Pts with epidermal growth factor receptor mutations, anaplastic lymphoma kinase rearrangements, or whose first-line systemic therapy was molecular targeted therapy were excluded. Results: A total of 1245 pts were enrolled: median (range) age 78 (75-95) years; 278 (22%) female; 367 (29%) ECOG PS 0, 680 (55%) PS 1 and 171 (14%) PS 2; 678 (54%) adenocarcinoma; PD-L1 tumor proportion score 268 (22%) &lt;1%, 387 (31%) 1-49% and 410 (34%) ≥50%; 354 (28%) ICI-chemo, 425 (34%) ICI alone, 311 (25%) platinum-doublet chemotherapy and 155 (12%) single agent chemotherapy. The median overall survival (OS) was 20.0 months (95%CI, 17.1–23.6) in the ICI-chemo group, 19.8 months (95%CI, 16.5–23.8) in the ICI alone group, 12.8 months (95%CI, 10.7–15.6) in the platinum-doublet chemotherapy group and 9.5 months (95%CI, 7.4–13.4) in the single agent chemotherapy group, respectively. After propensity score matching, there was no difference in OS and progression-free survival (PFS) between ICI-chemo group (n=96) and ICI alone group (n=95) in PD-L1 ≥1% (OS: HR, 0.98; 95% CI, 0.67-1.42, PFS: HR, 0.92; 95% CI, 0.67-1.25). Regardless of PD-L1 subgroups (1-49% or ≥50%), no significant differences in OS and PFS were observed. Concerning safety, Grade 3 or higher immune-related adverse events (irAEs) occurred in 86 pts (24.3%) in the ICI-chemo group and 76 pts (17.9%) in the ICI alone group (p = 0.03). The number of pts who required steroids for irAEs was 115 (32.5%) in the ICI-chemo group and 105 (24.7%) in the ICI alone group (p = 0.02). Pneumonitis was reported in 83 pts (23.4%) in the ICI-chemo group and 66 pts (15.6%) in the ICI alone group (p = 0.006). Conclusions: In real-world data for pts aged 75 years or older, ICI-chemo did not improve survival and increased the incidence of grade 3 or higher irAEs compared to ICI alone. Based on our results, ICI alone is recommended for elderly pts with PD-L1 positive NSCLC. Clinical trial information: UMIN000046700 .

NeoCOAST-2: A phase 2 study of neoadjuvant durvalumab plus novel immunotherapies (IO) and chemotherapy (CT) or MEDI5752 (volrustomig) plus CT, followed by surgery and adjuvant durvalumab plus novel IO or volrustomig alone in patients with resectable non-small-cell lung cancer (NSCLC).

TPS8604 Background: Neoadjuvant platinum-based CT plus IO prolongs event-free survival (EFS) and increases pathological complete response (pCR) rate in patients with resectable NSCLC vs CT alone (Forde et al. N Engl J Med 2022). IO+IO+CT combinations have the potential to further improve pCR and survival outcomes. The phase 2 NeoCOAST-2 study (NCT05061550) is evaluating multiple neoadjuvant IO+IO+CT combinations in patients with resectable, early stage NSCLC. Novel IO molecules being evaluated include the anti-CD73 monoclonal antibody (mAb), oleclumab; the anti-NKG2A mAb, monalizumab; and the PD-1/CTLA-4 bispecific mAb, volrustomig. The latter recently demonstrated durable responses vs a PD-1 inhibitor plus CT as first-line treatment for patients with metastatic NSCLC (ESMO 2022; LBA56). Here we describe the NeoCOAST-2 study design. Methods: This randomized, open-label, multicenter study will enrol approximately 210 patients with previously untreated, histologically/cytologically confirmed, resectable Stage IIA–IIIB (AJCC 8th edition) NSCLC. Patients will be stratified by PD-L1 expression ( &lt; 1% vs ≥1%) and receive treatment with durvalumab + oleclumab + CT, durvalumab + monalizumab + CT, or volrustomig + CT every 3 weeks for 4 cycles prior to surgery, followed by adjuvant durvalumab + oleclumab, durvalumab + monalizumab, or volrustomig for up to 1 year or until disease progression per RECIST v1.1. Surgery should occur within 40 days after the last dose of neoadjuvant therapy and adjuvant therapy should commence within 10 weeks after surgery. The primary endpoints are pCR rate (per blinded independent pathologist review) and safety and tolerability. Secondary endpoints include investigator-assessed EFS, disease-free survival and overall survival, feasibility to surgery, major pathological response rate, objective response rate following neoadjuvant therapy, pharmacokinetics, immunogenicity, and changes in circulating tumor DNA. The study is currently recruiting patients across the US, Europe, Canada, and Asia. Clinical trial information: NCT05061550 .

Exploration of biomarkers in potentially resectable stage IIIB NSCLC patients receiving neoadjuvant chemoimmunotherapy.

e20591 Background: Non–small cell lung cancer (NSCLC) is one of the main leading causes of cancer mortality in the world. NSCLC is incurable in most patients with potentially resectable locally advanced stage IIIB disease. Numerous studies suggest that advantageous chemoimmunotherapy is a promising treatment for resectable NSCLC. The determination of PD-L1, T-cell receptor (TCR) repertoire and tumor mutational burden (TMB) have been reported to predict the response to immunotherapy. However, the value of pathologic response determination in the context of neoadjuvant chemoimmunotherapy in resectable stage IIIB NSCLC is limited. Therefore, it is necessary to identify biomarkers for the prediction of the benefit from neoadjuvant chemoimmunotherapy in patients with potentially resectable stage IIIB NSCLC. Methods: A total of 15 patients with potentially resectable clinical stage IIIB NSCLC were enrolled into the study receiving neoadjuvant sintilimab (200mg IV Q3W) plus chemotherapy therapies for 4-6 weeks followed by surgery. All peripheral blood and tissue samples were collected and detected by using TCR repertoire sequencing before and after chemoimmunotherapy. The patients were divided into MPR group (n=5) and non-MPR group (n=10) according to MPR (&lt;10% viable tumour at resection) as an index. Furthermore, TMB spectra of 1021-gene panels and PD-L1 immunohistochemical staining were performed in paraffin-embedded human NSCLC tissue before neoadjuvant chemoimmunotherapy. The Pearson correlation coefficient method was used to analyze correlation. The ROC analysis were performed using “pROC” R package. Results: In baseline tissue samples, the levels of TMB and NAD were higher in MPR compared with non-MPR groups (P=0.0328, P=0.015, respectively). The negative correlation was existed between pretreatment tissue TCR richness and TMB in non-MPR group (P=0.028, R=-0.66). In MPR group, TCR clones and evenness showed significant difference (P=0.00237, P=0.04658, respectively). In non-MPR group, the TCR repertoire of tissue in posttreatment showed significant difference compared with those of pretreatment, including clones (P=1.04x10-6), shannon’s diversity (P=0.00142), evenness (P=0.00433), richness (P=0.00591). The clinical data showed that MPR patients with DDR mutation had longer DFS after sintilimab plus chemotherapy therapies (18.4±5.41 months, X-squared=9.8, P=0.02034). DDR mutation, TMB and TCR richness revealed better sensitivity and specificity to classify patients achieving MPR after neoadjuvant chemoimmunotherapy (AUC=1.000, AUC=0.796, AUC=0.773, respectively). Conclusions: This study confirmed the superiority of neoadjuvant chemoimmunotherapy in patients with potentially resectable stage IIIB NSCLC in terms of MPR. TCR repertoire, TMB and DDR mutation were associated with pathologic response to neoadjuvant chemoimmunotherapy as biomarkers for effective anti-tumor immunity. Clinical trial information: ChiCTR2000040673 .

Characteristics of lung cancer in renal transplant recipients.

e20592 Background: Renal transplant recipients (RTRs) are at a higher risk of developing malignancies primarily due to prolonged immunosuppression. Lung cancer while rare in RTR, is associated with significant morbidity and mortality. The primary objective of our study is to analyze the clinical characteristics and outcomes of RTRs who developed lung cancer at our institution. Methods: We retrospectively reviewed 1998 RTRs who underwent transplantation between January 1, 1999, and December 31, 2019, at our institution and identified patients who were diagnosed with lung cancer after transplant. Baseline demographic variables and information related to the renal transplant, the diagnosis and management of lung cancer were collected. Results: Among 1998 RTRs, 10 patients (0.005%) developed lung cancer. A majority of the lung cancer patients identified as male (n = 8), and the median age was 62.5 years. The races of the patients were white (30%, n = 3), African American (50%, n = 5), Hispanic (10%, n = 1), and Native American (10%, n = 1). Concomitant liver transplant was performed in 2 patients, and a concomitant heart transplant was performed in 1 patient. Median time to lung cancer diagnosis after transplant was 67.5 months (range, 12-168). The histology of the lung cancers found were adenocarcinoma (n = 4), squamous (n = 4), and small cell (n = 2). All patients had a history of smoking, with 90% reporting a &gt; 15 pack-year history of smoking and none of them received lung cancer screening. Among the patients with non-small cell lung cancer (NSCLC), 87.5% (n = 7) had early-stage disease, and 12.5% (n = 1) had locally advanced disease (Stage IIIB). Both patients diagnosed with small cell lung cancer had extensive-stage (es-SCLC) disease at the time of diagnosis. Among patients with NSCLC, 2 had genomic tumor profiling performed. Among patients with early-stage NSCLC, 57% underwent upfront surgery, 14% received radiation alone, 14% received neoadjuvant chemotherapy, and 14% received adjuvant chemotherapy. Around 71% (n = 5) remained alive at the last follow up recorded. The patient with stage IIIB NSCLC received chemotherapy and concomitant radiation but had an overall survival (OS) of only 6 months; that patient died of complications related to cancer progression. Both patients with es-SCLC received front-line chemotherapy with carboplatin and etoposide. To our knowledge, 40% (n = 4) of these patients retained their renal graft function. At 1-year from diagnosis, 40% of patients diagnosed with lung cancer were still alive. Conclusions: Lung cancer in RTRs is rare but is associated with significant morbidity and mortality. With the improving life expectancy of RTRs, the incidence of de novo malignancies including lung cancer is likely to increase. Annual screening for lung cancer in high-risk individuals is an important step for early diagnosis. Surgical resection and chemotherapy are well tolerated in patients with lung cancer.

Stereotactic body radiation therapy with sequential immunochemotherapy as neoadjuvant therapy in resectable non-small cell lung cancer (SACTION-01 study).

8540 Background: Neoadjuvant PD-1 inhibitor plus chemotherapy increases pathological response for resectable non-small cell lung cancer (NSCLC) compared with chemotherapy alone. Previous phase II trial indicated that stereotactic body radiation therapy (SBRT) served as an immunomodulator and enhanced the effect of preoperative immuno-monotherapy. However, whether SBRT would further increase the efficacy of immunochemotherapy for NSCLC remains unknown. Methods: In this phase II trial, patients with resectable EGFR wild-type stage IIA to IIIB NSCLC were recruited to receive SBRT (24 Gy in 3 daily fractions) to the primary tumor followed by two cycles of PD-1 inhibitor tislelizumab (200 mg) plus platinum-based doublet chemotherapy (Q3W) before surgical resection. The primary endpoint was major pathological response (MPR) defined as no more than 10% of viable tumor cells in the specimen. Simon’s optimal two-stage design was used for conducting the trial. The null hypothesis was that the MPR rate is 0.30, and the alternative hypothesis was that the true MPR rate was 0.50. More than 4 MPRs were needed in stage 1 (n=15) to continue, and if there were 19 or more MPRs in 46 patients by the end of stage 2, the null hypothesis can be rejected. The design controls the type I error rate at 0.05 and yields the power of 0.80. (NCT05319574). Results: Between May 2022 and Jan 2023, 32 patients were enrolled with 31 (96.9%) male and 19 (59.4%) having squamous cell lung cancer. Twenty-six (81.3%) patients had stage IIIA/B disease. All patients received at least one cycle of immunochemotherapy; 23 of the 25 patients (92.0%) who completed treatment had undergone R0 resections, except for one patient who had disease progression and the other one that unable to tolerate surgery because of grade 4 neutropenia. Twenty-two patients underwent minimally invasive approaches and 3 of them (13.6%) converted to thoracotomy. The median percentage of the viable tumor was 0 (interquartile range: 0-4.0%). Twenty patients achieved MPR, which surpassed the prespecified required number to reject the null hypothesis, resulting in the MPR rate of 80.0% (20/25) in the intention-to-treat population, and 87.0% (20/23) in the per-protocol population. Pathological complete response (pCR) was found in 14 patients (56.0% in the intention-to-treat population and 60.9% in the per-protocol population). Nodal clearance status (pN0) was found in 20 of 23 cN1/2 cases (87.0%). Grade 3-4 adverse events related to neoadjuvant treatment included neutropenia (13.0%), anemia (4.3%), and pneumonia (4.3%). No 30-day or 90-day mortality was observed. Conclusions: Neoadjuvant SBRT followed by immunochemotherapy yields unprecedently high MPR and pCR rates in NSCLC without EGFR mutation. The trial will continue to recruit 14 more patients to reach a final sample size of 46 participants. Clinical trial information: NCT05319574 .

Pathological response and tumor immune microenvironment remodeling of neoadjuvant ALK-TKIs in NSCLC with ALK.

e20574 Background: Anaplastic lymphoma kinase–tyrosine kinase inhibitor (ALK-TKI; ALKi) has shown potent antitumor activity in metastatic non–small-cell lung cancer (NSCLC) with ALK rearrangement (ALK+). However, its efficacy in neoadjuvant settings for patients with ALK+ resectable NSCLC has been poorly explored. Given this, the present study aimed to examine the clinical activity and tumor immune microenvironment (TIME) remodeling of neoadjuvant ALKi therapy. Methods: In this retrospective study, ALK+ NSCLC patients treated with neoadjuvant ALKi therapy at three hospitals in China were enrolled between February 2018 and April 2022.Data on clinical features, radiographic responses, and pathological responses were collected and evaluated. Multiplex immunofluorescence was performed on pre-treatment biopsy specimens and surgically resected specimens to investigate the impact of ALKi on TIME. Two panels (Panel 1: CD8, PD1, GB, CK, 4′,6-diamidino-2-phenylindole [DAPI]; Panel 2: CD4, FOXP3, CD68, CD163, CK, DAPI) were used to identify multiple immune cell types. Results: A total of 12 patients with stage IIA to IIIB NSCLC who received neoadjuvant ALKi therapy and R0 resection were enrolled; the median age was 54.0 years, and 66.7% (8/12) were female. The median duration of neoadjuvant ALKi was 5.5 months. The objective response rate was 91.7% (11/12). All patients successfully underwent R0 resection. The major pathological response (MPR) rate was 75.0% (9/12), with 58.3% (7/12) achieving a pathological complete response (pCR). After neoadjuvant ALKi therapy, we observed asignificant increase in immune infiltration of total CD8+ (histochemistry score: median, 10.51 vs 24.01, P= 0.028; density: median, 128.38 vs 694.09 cells/mm2, P= 0.028; percentage: median, 3.53% vs 15.92%, P= 0.028) and total CD4+ (density: median, 275.56 vs 651.82 cells/mm2, P= 0.028; percentage: median, 5.98% vs 10.46%, P= 0.028). Similar results were found for CD4+FOXP3+, CD8+PD1+, CD8+PD1-, CD8+GB+, and CD8+GB-. However,macrophages, including CD68+CD163- M1 and CD68+CD163+ M2 macrophages, showed little change after neoadjuvant ALKi therapy. When comparing TIME between neoadjuvant ALKi and PD1 inhibitors in resected specimens from patients with pCR, neoadjuvant ALKi therapy presented higher levels of CD8+PD1+ but lower levels of CD8+GB+. Conclusions: Neoadjuvant ALKi therapy achieved an encouraging MPR rate of 75% and enhanced immune infiltration, suggesting its safety and feasibility for ALK+ resectable NSCLC. This study advances our understanding of TIME remodeling by neoadjuvant ALKi therapy and merits further investigation in the neoadjuvant setting for patients with ALK+ resectable NSCLC.

Neoadjuvant immunotherapy plus chemotherapy and adjuvant targeted therapy in ALK-positive non-small-cell lung cancer.

Neoadjuvant therapy and adjuvant therapy for locally advanced non-small-cell lung cancer (NSCLC) with ALKfusion mutation have not been thoroughly studied. Here, a stage IIIB NSCLC patient with EML4-ALK fusion mutation receiving immunotherapy plus chemotherapy as neoadjuvant treatment followed by lobectomy plus lymph node dissection is reported. The patient achieved a pathological complete responseaccording to pathological evaluation. The patient received adjuvant crizotinib for 3months and achieved a disease-free survival time of 36months.

Comparative Study of Hypofractionated Palliative Radiotherapy 17 Gy in 2 Fractions vs. 30 Gy in 10 Fractions in Lethal Locally Advanced Non-small Cell Lung Cancer

<i>Background</i>: Lung cancer kills the most people worldwide. Most Bangladeshi patients had regionally advanced surgically inoperable Non-Small Cell Lung Cancer (NSCLC), a deadly disease. Radiotherapy to main tumor and regional lymphatics with chemotherapy is conventional treatment. <i>Objective</i>: This study was done to investigate the symptoms relief and treatment related toxicities in hypo fractionated 17 Gy in 2 fractions which is effectively comparable to 30 Gy in 10 fractions. <i>Methods</i>: A total 60 patients were divided equally into Arm A and Arm B with locally advanced stage IIIA, and stage IIIB NSCLC patients with the objective to compare palliation of symptoms and to assess the toxicity profile. This Quasi Experimental study was carried out from January 2018 to December 2018 in the department of Radiation oncology, National Institute of Cancer Research and Hospital. Cases of Arm A were treated with 17 Gy radiotherapy in 2 fractions and those of Arm B were treated with 30 Gy radiotherapy in 10 fractions. <i>Results</i>: The mean age was 49.3±8.8 and 52.2±8.1 years for the Arm- A and the Arm-B respectively. Most patients in both groups were males, 80% in group A and 90% in group B. Adenocarcinoma (Arm A-70%, Arm B- 66.7%) was the most common pathological subtype in both groups, followed by Squamous cell carcinoma (30%, 33.3% respectively). This study showed that there was a significant palliation of these symptoms following radiotherapy as reported by patients and as assessed clinically with no statistically significant difference between two Arms. Hemoptysis had the highest rate of improvement, 100% in both arms and improvement in chest pain by 83.3% in arm A and 70% in Arm B. Cough was improved in 83.3% and 67.7% and dyspnea was palliated in 80.0% and 70.0% of patients in Arm A and Arm B, respectively as per clinical assessment of the patients. The early toxicities in both arms had no significant difference. Patients with locally advanced inoperable NSCLC have poor prognosis and less survival. The first goal was acceptable symptoms control as cough, dyspnoea, haemoptysis and chest pain. <i>Conclusion</i>: The result of this study showed that a significant palliation of symptoms with minimum toxicities improving quality of life following radiotherapy as reported by patients also assessed clinically and radiographically with no statistically significant difference among both arms.

Abstract CT215: Efficacy and safety of adjuvant (adj) atezolizumab (atezo) from the Phase 2 LCMC3 study

Abstract Background LCMC3 (NCT02927301), an open-label, single-arm Phase 2 study to investigate neoadjuvant (neoadj) and adj atezo (anti-PD-L1) in patients (pts) with early-stage non-small cell lung cancer (NSCLC), met its primary endpoint with a 20% major pathological response (MPR) rate after neoadj atezo. Here we report efficacy and safety from the adj phase. Methods Eligible pts aged ≥18 y had resectable stage IB-IIIA or select IIIB NSCLC and ECOG PS of 0 or 1. Pts received neoadj atezo 1200 mg IV for ≤2 cycles (Days 1 and 22) followed by surgery (Day 40±10). Pts deemed to have clinical benefit were offered the option to receive adj atezo every 3 weeks for up to 12 months. The primary endpoint was MPR rate (≤10% viable tumor cells at surgery) in pts without EGFR/ALK mutations. Exploratory endpoints included DFS and OS. Safety was assessed during the adj phase. Results Data cutoff was Oct 21, 2022. The primary efficacy population (PEP) was 137 pts without EGFR/ALK alterations who had surgery and MPR assessment. In the PEP, 53 pts (39%) received adj atezo and 84 (61%) did not. The 3-y DFS rate was 83% with adj atezo vs 64% without (HR, 0.43; 95% CI: 0.21, 0.90; P=0.025). 3-y OS and results by MPR status are provided in the table. In the adj atezo safety population (n=57), treatment-related (TR) AEs after adj atezo occurred in 55 pts (97%; Gr 3/4, 40%), including 11 TRAEs (19%; Gr 3/4, 16%) leading to discontinuation of adj atezo. No Gr 5 TRAEs were seen in the adj phase. Multivariate analysis also showed a trend toward better DFS for pts receiving adj atezo vs those with no adj atezo (HR, 0.52; 95% CI: 0.22, 1.21; P=0.126). Conclusions This exploratory analysis revealed that LCMC3 pts with resectable stage IB-IIIA or select IIIB NSCLC who received adj atezo had improved DFS and showed a trend toward improved OS vs pts who did not receive adj atezo. Furthermore, the non-MPR subgroup had the same trend toward improved DFS and OS with adj atezo vs pts who did not receive adj atezo. Adj atezo was well tolerated, with no new safety concerns. Table Adj atezoa n=53 No adj atezob n=84 Tx patterns Adj atezo + adj chemo, n (%) 17 (32) 0 Adj atezo, n (%) 36 (68) 0 Adj chemo, n (%) 0 36 (43) None, n (%) 0 48 (57) Tx cycles Adj atezo, n, median (range) 53, 16 (1-18) 0 Adj chemo, n, median (range) 16, 3 (0-4.2) 35, 3 (0-4.1) HR (95% CI) P PEP (N=137) 3-y DFS, % 83 64 0.43 (0.21, 0.90) 0.025 3-y OS, % 89 77 0.48 (0.19, 1.21) 0.118 MPR (n=29) n=22 n=7 3-y DFS, % 86 86 0.93 (0.10, 8.92) 0.948 Non-MPR (n=108) n=31 n=77 3-y DFS, % 80 62 0.48 (0.20, 1.12) 0.088 3-y OS, % 87 75 0.49 (0.17, 1.46) 0.202 Multivariable Cox regression (n=114)c MPR vs non-MPR 0.37 (0.11, 1.31) 0.125 Adj atezo vs no adj atezo 0.52 (0.22, 1.21) 0.126 Adj chemo vs no adj chemo 0.57 (0.27, 1.19) 0.133 Stage I/II vs III 0.71 (0.35, 1.43) 0.338 PD-L1 tumor proportion score ≥1% vs &amp;lt;1% 1.09 (0.54, 2.21) 0.805 Tx, treatment. aReceived adj atezo or adj atezo + adj chemo. bReceived adj chemo or no adj treatment. cOverall likelihood ratio test P=0.097 for the model. Citation Format: David Paul Carbone, Saiama N. Waqar, Jamie E. Chaft, Mark G. Kris, Bruce E. Johnson, Jay M. Lee, Ignacio I. Wistuba, David Kwiatkowski, Paul Bunn, Katja Schulze, Ann Johnson, Evelise Brandao, Mark Awad, Karen L. Reckamp, Anne C. Chiang, Alan Nicholas, Valerie Rusch. Efficacy and safety of adjuvant (adj) atezolizumab (atezo) from the Phase 2 LCMC3 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT215.

116P Survival outcome of chemotherapy in stage IIIA and IIIB non-small cell lung cancer

116P Survival outcome of chemotherapy in stage IIIA and IIIB non-small cell lung cancer

Human Papillomavirus in Non-Small Cell Lung Carcinoma: Assessing Virus Presence in Tumor and Normal Tissues and Its Clinical Relevance.

the study involved 274 patients with stage IIA-IIIB non-small cell lung cancer. We analyzed normal and tumor tissues as well as blood from each patient. DNA was extracted from patients' specimens, and HPV detection and genotyping was carried out using commercially available kits by PCR. HPV was detected in 12.7% of the patients (35/274 of all cases). We detected nine different types of human papillomavirus in the patients, namely, types 16, 18, 31, 35, 45, 51, 52, 56, and 59. The HPV-positive samples had a clinically insignificant viral load and were predominantly integrated. The relationship between the presence of HPV and its virological parameters and the clinical and pathological parameters of the patients was established. A metastatic-free survival analysis showed that all patients with HPV in the tumor tissue had a higher 5-year survival rate (94%) compared with the HPV-negative patients (78%). The result was not statistically significant (p = 0.08). data showing a 12.7% human papillomavirus representation among patients with non-small cell lung cancer were obtained. The presence/absence of a viral component in patients with lung cancer was a clinically significant parameter. HPV types 16, 18, and 56, which are the most oncogenic, were most often detected.

Multiplex immunofluorescence and single-cell transcriptomic profiling reveal the spatial cell interaction networks in the non-small cell lung cancer microenvironment.

Conventional immunohistochemistry technologies were limited by the inability to simultaneously detect multiple markers and the lack of identifying spatial relationships among cells, hindering understanding of the biological processes in cancer immunology. Tissue slices of primary tumours from 553 IA∼IIIB non-small cell lung cancer (NSCLC) cases were stained by multiplex immunofluorescence (mIF) assay for 10 markers, including CD4, CD38, CD20, FOXP3, CD66b, CD8, CD68, PD-L1, CD133 and CD163, evaluating the amounts of 26 phenotypes of cells in tumour nest and tumour stroma. StarDist depth learning model was utilised to determine the spatial location of cells based on mIF graphs. Single-cell RNA sequencing (scRNA-seq) on four primary NSCLC cases was conducted to investigate the putative cell interaction networks. Spatial proximity among CD20+ B cells, CD4+ T cells and CD38+ T cells (r2 =0.41) was observed, whereas the distribution of regulatory T cells was associated with decreased infiltration levels of CD20+ B cells and CD38+ T cells (r2 =-0.45). Univariate Cox analyses identified closer proximity between CD8+ T cells predicted longer disease-free survival (DFS). In contrast, closer proximity between CD133+ cancer stem cells (CSCs), longer distances between CD4+ T cells and CD20+ B cells, CD4+ T cells and neutrophils, and CD20+ B cells and neutrophils were correlated with dismal DFS. Data from scRNA-seq further showed that spatially adjacent N1-like neutrophils could boost the proliferation and activation of T and B lymphocytes, whereas spatially neighbouring M2-like macrophages showed negative effects. An immune-related risk score (IRRS) system aggregating robust quantitative and spatial prognosticators showed that high-IRRS patients had significantly worse DFS than low-IRRS ones (HR 2.72, 95% CI 1.87-3.94, p<.001). We developed a framework to analyse the cell interaction networks in tumour microenvironment, revealing the spatial architecture and intricate interplays between immune and tumour cells.

Neoadjuvant Immunotherapy in Oncogene-Positive Non-Small Cell Lung Cancer: A Multicenter Study

BackgroundPreoperative immunotherapy has shed light on the management of resectable non-small cell lung cancer (NSCLC). However, whether neoadjuvant immunotherapy benefits patients with oncogene-positive NSCLC remains unknown. MethodsData were retrieved from 4 institutions in the period from August 2018 to May 2021. Eligible patients were aged ≥18 years with histologically confirmed stage IIA to stage IIIB (T1-2 N1-2 or T3-4 N0-2) NSCLC that was deemed to be surgically resectable. The neoadjuvant regimen included immune checkpoint inhibitors alone or in combination with platinum-based doublets. Surgical resection was performed 4 to 6 weeks after the first day of the last cycle of treatment. The primary end point was major pathologic response (MPR; ≤10% viable tumor cells). Analyses were categorized according to the patients’ oncogene (EGFR, ALK, KRAS, MET, BRAF, ROS1, RET) status. ResultsOverall, 137 patients were identified; 46 (33%) patients had nonsquamous cell cancer, and 114 (83%) had stage IIIA/B disease. Oncogene alterations were identified in 22 (16%) patients, of whom only 2 patients (2/22 [9%]) had an MPR compared with 65 (65/115 [56.5%]) in the oncogene-negative population (P < .001). Similar results were retained after propensity score matching for age, sex, smoking status, histologic type, stage, and cycles of neoadjuvant treatment. Squamous cell carcinoma (odds ratio, 2.54; 95% CI, 1.08-5.99) and positive oncogene status (odds ratio, 0.13; 95% CI, 0.03-0.64) were found to be indicators for MPR by logistic regression. The 1-year event-free survival rate was 75.4% in the oncogene-positive group, which was not significantly different from 85.5% in the oncogene-negative population (P = .23). ConclusionsPatients with stage II-III oncogene-positive NSCLCs respond less than patients with oncogene-negative NSCLCs after neoadjuvant immunotherapy.

The Validation of Predictive Risk Scoring Model of Radiation Pneumonitis (RP) in Lung Cancer Patients

<h3>Purpose/Objective(s)</h3> In our previous research, pulmonary emphysema (PE) was reported as a risk factor of radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC). Subclinical interstitial lung disease (SILD) was associated with severe RP in small cell lung cancer patients. A predictive risk scoring model of RP was developed in stage IIIA or Stage IIIB NSCLC patients receiving radical radiotherapy. The risk score has not been validated using an independent dataset. The aim of this study was to validate the predictive risk score which established in our previous study and evaluate the predictive value of the model. <h3>Materials/Methods</h3> From January 2019 to October 2021,129 lung cancer patients were recruited in study which included in validation group. Those patients were received thoracic radiotherapy with ≥50Gy total radiotherapy dose. The risk scoring model in our previous research as follow: PRS=5 (if subclinical ILD grade≥1) + 3 (if age >68 years) + 3 (if PE grade >1). According to the risk score, the cases in validation group were scored, predictive value of this model were evaluated by receiver operator characteristic curve (ROC) using statistical software. The decision curve analysis was constructed using Stata 17.0 software. <h3>Results</h3> In 129 eligible patients, 13(10.08%, 13/129) developed grade 1 RP, 15(11.62%, 15/129) developed grade 2 RP, grade 3 and grade 4 RP were not observed. 23 (16.60%, 23/129) had PE grade >1. Risk scores of all patients were calculated according to the risk score, 37 had 3 points which incidence of RP ≥2 grade was 13.50%, 2 had 5 points which incidence of RP ≥2 grade was 100.0%, 3 had 6 points which incidence of RP ≥2 grade was 33.33%. ROC curve was plotted according to the risk score of all patients, the area of ROC curve (AUC) was 0.695 (95%CI: 0.541-0.849, P < 0.05). The decision curve indicated that the net benefit of the model was higher in the high-risk threshold of 0.2-0.3. <h3>Conclusion</h3> The previous predictive risk scoring model indicated good discrimination and clinical application value, which can be used in clinical treatment.

Pembrolizumab leading to complete resolution of non-small cell lung cancer and microsatellite instability stable colon adenocarcinoma; two birds one stone

Introduction: Staging of non-small cell lung cancer is crucial in predicting patient prognosis and more importantly, determining cancer management. In patients without driver mutations, PD-L1 tumor proportion score evaluation becomes vital in dictating treatment, as immunotherapy can be recommended. These agents have been shown to lead to excellent outcomes, even in patients with late-stage disease. Case Report: A 69-year-old male with a history of chronic obstructive pulmonary disease (COPD) presented with worsening dyspnea found to have lung collapse from a large hilar soft tissue mass causing obstruction of the left mainstem bronchus. After malignancy workup, the patient was diagnosed with non-small cell lung cancer clinically staged as IIIB. An incidental finding of microsatellite instability colon cancer was also found during workup. Pembrolizumab treatment was initiated and led to near resolution of both tumors. Conclusion: Stage IIIB non-small cell lung cancer has an overall poor prognosis. Biomarker testing in our case prior to starting concurrent chemoradiation revealed the malignancy to have a 100% tumor proportion score for PD-L1, the fundamental reason why our patient’s treatment was successful. Based on our findings, we advocate for all patients with non-small cell lung cancer regardless of stage to undergo biomarker testing prior to therapy initiation. Furthermore, the resolution of PD-L1 negative microsatellite instability stable colon cancer after pembrolizumab therapy supports further investigation of the utility and mechanism of PD-1/PD-L1-based therapy in PD-L1 negative colon cancer.

Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial

In an ongoing, open-label, single-arm phase II study (NCT02927301), 181 patients with untreated, resectable, stage IB–IIIB non-small cell lung cancer received two doses of neoadjuvant atezolizumab monotherapy. The primary end point was major pathological response (MPR; ≤10% viable malignant cells) in resected tumors without EGFR or ALK alterations. Of the 143 patients in the primary end point analysis, the MPR was 20% (95% confidence interval, 14–28%). With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80% was encouraging. The most common adverse events during the neoadjuvant phase were fatigue (39%, 71 of 181) and procedural pain (29%, 53 of 181), along with expected immune-related toxicities; there were no unexpected safety signals. In exploratory analyses, MPR was predicted using the pre-treatment peripheral blood immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive of MPR in the peripheral blood were also identified in the tumor microenvironment and were associated with MPR. This study of neoadjuvant atezolizumab in a large cohort of patients with resectable non-small cell lung cancer was safe and met its primary end point of MPR ≥ 15%. Data from this single-arm, non-randomized trial suggest that profiles of innate immune cells in pre-treatment peripheral blood may predict pathological response after neoadjuvant atezolizumab, but additional studies are needed to determine whether these profiles can inform patient selection and new therapeutic approaches.

Dose-response relationship between epidural bupivacaine dose and mortality risk after surgical resection of nonsmall-cell lung cancer.

Preclinical studies have shown that local anesthetics may modify the growth and invasion of cancer cells. However, few clinical studies have evaluated their impact on cancer outcomes after tumor resection. In this single-center cohort study, patients who underwent surgical resection of stage IA through IIIB nonsmall-cell lung cancer and used patient-controlled epidural analgesia from 2005 to 2015 were recruited and followed until May 2017. Data of the epidural bupivacaine dose for each patient were obtained from infusion pump machines. Proportional hazards regression models were used to analyze the associations between bupivacaine dose with postoperative cancer recurrence and all-cause mortality. A total of 464 patients were analyzed. Among these patients, the mean bupivacaine dose was 352 mg (± standard deviation 74 mg). After adjusting for important clinical and pathological covariates, a significant dose-response relationship was observed between epidural bupivacaine dose and all-cause mortality (adjusted hazard ratio: 1.008, 95% confidence interval: 1.001-1.016, p = 0.029). The association between bupivacaine dose and cancer recurrence were not significant (adjusted hazard ratio: 1.000, 95% confidence interval: 0.997-1.002, p = 0.771). Age, sex, body mass index, mean daily maximum pain score, and pathological perineural infiltration were independently associated with bupivacaine dose. A dose-dependent association was found between epidural bupivacaine dose and long-term mortality among patients following surgical resection of nonsmall-cell lung cancer. Our findings do not support the hypothetical anticancer benefits of local anesthetics. More studies are needed to elucidate the role of local anesthetics in cancer treatment.