IIIB Non-small Cell Lung Cancer Research Articles

Cemiplimab (Libtayo)

CADTH recommends that Libtayo in combination with platinum-based chemotherapy be reimbursed by public drug plans for the first-line treatment of adults with non–small cell lung cancer (NSCLC) whose tumours have no EGFR, ALK, or ROS1 aberrations and is locally advanced where patients are not candidates for surgical resection or definitive chemoradiation, or for those with metastatic NSCLC, if certain conditions are met. Libtayo in combination with platinum-based chemotherapy should only be covered to treat adults who have stage IIIB or IIIC NSCLC and are not suitable for curative surgery or definitive chemoradiation or have stage IV NSCLC and have not received prior systemic treatment. Patients’ tumours should have no EGFR, ALK, or ROS1 Patients should have a good performance status. Libtayo should only be reimbursed in combination with platinum-based chemotherapy if prescribed by clinicians with expertise and experience in treating NSCLC. The treatment should be delivered in outpatient specialized oncology clinics with expertise in systemic therapy delivery and management of immunotherapy-related side effects. The price of Libtayo should be negotiated so that its use in combination with platinum-based chemotherapy does not exceed the total drug cost of treatment with the least costly immunotherapy reimbursed in the first-line setting.

Perioperative Nivolumab in Resectable Lung Cancer

BackgroundStandard treatment with neoadjuvant nivolumab plus chemotherapy significantly improves outcomes in patients with resectable non–small-cell lung cancer (NSCLC). Perioperative treatment (i.e., neoadjuvant therapy followed by surgery and adjuvant therapy) with nivolumab may further improve clinical outcomes.MethodsIn this phase 3, randomized, double-blind trial, we assigned adults with resectable stage IIA to IIIB NSCLC to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was event-free survival according to blinded independent review. Secondary outcomes were pathological complete response and major pathological response according to blinded independent review, overall survival, and safety.ResultsAt this prespecified interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month event-free survival was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio for disease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% confidence interval [CI], 0.42 to 0.81; P<0.001). A pathological complete response occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio, 6.64; 95% CI, 3.40 to 12.97); a major pathological response occurred in 35.4% and 12.1%, respectively (odds ratio, 4.01; 95% CI, 2.48 to 6.49). Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group.ConclusionsPerioperative treatment with nivolumab resulted in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. No new safety signals were observed. (Funded by Bristol Myers Squibb; CheckMate 77T ClinicalTrials.gov number, NCT04025879.)

Clinical outcomes associated with neoadjuvant therapy for the treatment of resectable non-small cell lung cancer in real-world practice.

In order to improve survival outcomes in resectable non-small cell lung cancer (NSCLC), strategies for neoadjuvant therapy need to be revisited. We evaluated and compared the efficacy of different neoadjuvant therapeutic modalities in a real-world setting. A total of 258 patients with clinical stage IIA to IIIB NSCLC was included. All the patients underwent surgical resection after one to four cycles of neoadjuvant treatment consisting of chemotherapy (83), immunotherapy (23), and immunotherapy plus chemotherapy (152). The radiologic response rate in the combined immunochemotherapy group was 67.8%, higher than that of 48.2% in the chemotherapy group and 4.3% in the immunotherapy group (p < 0.001). An improved major pathological response (MPR) was also achieved in the combined therapy group compared with the chemotherapy group and the immunotherapy group (53.9% vs. 10.8% vs. 8.7%, p < 0.001). Patients in the combined therapy group had a significant trend toward longer disease-free survival than those in the chemotherapy alone group (3-year disease-free survival [DFS] of 68.79% vs. 50.81%; hazard ratio [HR] for progression or death, 0.477; p = 0.003). Multivariate Cox analysis identified radical surgery (HR, 0.328; p = 0.033), ypN0-1 stage (HR, 0.591; p = 0.038) and MPR result (HR, 0.362; p = 0.007) to be independent prognostic factors for DFS. Neoadjuvant treatment with a combination of immunotherapy plus chemotherapy appears to achieve higher radiological and pathological responses than monotherapy for IIA-IIIB NSCLC. Log-rank analysis showed that a better outcome could be expected in patients with the addition of immunotherapy to neoadjuvant chemotherapy if compared with patients with chemotherapy alone in terms of DFS.

Immunotherapy or Chemoimmunotherapy in Older Adults With Advanced Non–Small Cell Lung Cancer

Immune checkpoint inhibitor (ICI) plus chemotherapy combination treatment (ICI-chemotherapy) is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alterations, but there are few data on ICI-chemotherapy for patients 75 years and older. To inform the choice of first-line drugs in clinical practice and assess the safety and efficacy of ICI-chemotherapy combination treatment in older adult patients with previously untreated advanced NSCLC. This retrospective cohort study included 58 centers in Japan. The cohort consisted of patients 75 years and older with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC. Patients started first-line systemic therapy between December 2018 and March 2021. Those receiving first-line molecular targeted drugs were excluded. The data were analyzed from February 2022 to October 2022. Systemic therapy. The main outcomes were overall survival (OS), progression-free survival (PFS), and safety. A total of 1245 patients (median [range] age, 78 [75-95] years; 967 [78%] male) with NSCLC were included in the cohort. Programmed death ligand-1 (PD-L1) expression of less than 1% occurred in 268 tumors (22%); 1% to 49% in 387 tumors (31%); 50% and higher in 410 tumors (33%), and unknown expression in 180 tumors (14%). Median OS was 20.0 (95% CI, 17.1-23.6) months for the 354 patients receiving ICI-chemotherapy (28%); 19.8 (95% CI, 16.5-23.8) months for the 425 patients receiving ICI alone (34%); 12.8 (95% CI, 10.7-15.6) months for the 311 patients receiving platinum-doublet chemotherapy (25%); and 9.5 (95% CI, 7.4-13.4) months for the 155 patients receiving single-agent chemotherapy (12%). After propensity score matching, no differences in OS and PFS were found between the patients receiving ICI-chemotherapy vs ICI alone. Each group consisted of 118 patients. For PD-L1 expression of 1% and higher the OS hazard ratio (HR) was 0.98 (95% CI, 0.67-1.42; P = .90), and the PFS HR was 0.92 (95% CI, 0.67-1.25; P = .59). Significance was also not reached when separately analyzed for lower or higher PD-L1 expression (1%-49% or ≥50%). However, grade 3 or higher immune-related adverse events occurred in 86 patients (24.3%) treated with ICI-chemotherapy and 76 (17.9%) with ICI alone (P = .03). In this study, ICI-chemotherapy combination treatment did not improve survival and increased the incidence of grade 3 and higher immune-related adverse events compared with ICI alone in patients 75 years and older. Based on these results, ICI alone may be recommended for older adult patients with PD-L1-positive NSCLC.

Real-World Neoadjuvant Treatment Patterns and Outcomes in Resected Non–Small-Cell Lung Cancer

BackgroundNovel neoadjuvant chemoimmunotherapy treatments are being investigated for locally advanced non–small-cell lung cancer (NSCLC), but real-world outcomes for neoadjuvant treatments are poorly understood. This study examined neoadjuvant treatment patterns, real-world event-free survival (rwEFS) and overall survival (OS) in patients with resected, stage II-III NSCLC in the United States (US). MethodsThis retrospective study identified patients in the SEER–Medicare database (2007-2019) with newly diagnosed stage II, IIIA, and IIIB (N2) NSCLC (AJCC 8th edition) treated with neoadjuvant chemo/chemoradiotherapy and resection (index date: neoadjuvant therapy initiation). Neoadjuvant treatment regimens were described. rwEFS (time from index to first recurrence or death, whichever occurred first) and OS (time from index to death) were summarized by Kaplan–Meier analysis for overall population, by disease stage at diagnosis, and by neoadjuvant treatment modality. Results221 patients (stage II, N=70; stage III, N=151) met eligibility criteria. The median follow-up from index was 32.7 months. All patients received neoadjuvant chemotherapy (51%) or chemoradiotherapy (49%) prior to surgery; 97% of patients received platinum-based regimens, among which carboplatin+paclitaxel was the most frequent (45%). In all patients, median rwEFS was 17.6 months and 5-year rwEFS was 20.9%; median OS was 48.5 months and 5-year OS was 44.9%. 71% of patients had disease recurrence during follow-up; among them, 28% developed locoregional recurrence as the first recurrence event. ConclusionsPatients with resected, stage II-III NSCLC who received neoadjuvant chemo/chemoradiotherapy have high rates of disease recurrence and poor survival outcomes, highlighting need for more effective treatments to improve survival rates.

Event-Free Survival as a Predictor of Overall Survival and Recurrence Burden of Patients with Non-Small Cell Lung Cancer Receiving Neoadjuvant Therapy

Event-free survival has replaced overall survival as a primary end point in many recent and ongoing clinical trials. This study aims to examine the correlation between real-world event-free survival and overall survival and to assess the clinical and economic burden associated with disease recurrence among patients with resected stage II to III non-small cell lung cancer who received neoadjuvant therapy in the United States. This retrospective study used the Surveillance, Epidemiology, and End Results Medicare database (2007-2019) to identify patients with newly diagnosed, resected, stage II to IIIB (N2) non-small cell lung cancer who received neoadjuvant therapy. The correlation between real-world event-free survival and overall survival was assessed using the normal scores rank correlation and landmark analysis. Overall survival, all-cause health care resource use and costs, and non-small cell lung cancer-related health care resource use and costs were compared between patients with and without recurrence. A total of 221 patients met the eligibility criteria (median follow-up time from neoadjuvant treatment initiation: 32.7months). The mean age was 72.1years, and 57.0% of patients were male. Real-world, event-free survival and overall survival are positively and significantly correlated (0.68; 95% CI, 0.52-0.79). Patients with recurrence had significantly shorter median overall survival (19.3 vs 116.9months), 4.59 times increased risk of death (95% CI, 2.56-8.26), and significantly higher all-cause and non-small cell lung cancer-related health care resource use and costs (adjusted mean monthly costs per patient difference: $5758 and $3187, respectively [all P<.001]). These findings help validate event-free survival as a clinically meaningful end point and strong predictor for overall survival and highlight the need for additional novel therapies that may delay or prevent recurrence in resectable stage II and III non-small cell lung cancer.

Deep pathomics: A new image-based tool for predicting response to treatment in stage III non-small cell lung cancer.

Despite the advantages offered by personalized treatments, there is presently no way to predict response to chemoradiotherapy in patients with non-small cell lung cancer (NSCLC). In this exploratory study, we investigated the application of deep learning techniques to histological tissue slides (deep pathomics), with the aim of predicting the response to therapy in stage III NSCLC. We evaluated 35 digitalized tissue slides (biopsies or surgical specimens) obtained from patients with stage IIIA or IIIB NSCLC. Patients were classified as responders (12/35, 34.7%) or non-responders (23/35, 65.7%) based on the target volume reduction shown on weekly CT scans performed during chemoradiation treatment. Digital tissue slides were tested by five pre-trained convolutional neural networks (CNNs)-AlexNet, VGG, MobileNet, GoogLeNet, and ResNet-using a leave-two patient-out cross validation approach, and we evaluated the networks' performances. GoogLeNet was globally found to be the best CNN, correctly classifying 8/12 responders and 10/11 non-responders. Moreover, Deep-Pathomics was found to be highly specific (TNr: 90.1) and quite sensitive (TPr: 0.75). Our data showed that AI could surpass the capabilities of all presently available diagnostic systems, supplying additional information beyond that currently obtainable in clinical practice. The ability to predict a patient's response to treatment could guide the development of new and more effective therapeutic AI-based approaches and could therefore be considered an effective and innovative step forward in personalised medicine.

TARGET: A Phase II, Open-Label, Single-Arm Study of 5-Year Adjuvant Osimertinib in Completely Resected EGFR-Mutated Stage II to IIIB NSCLC Post Complete Surgical Resection

IntroductionOsimertinib is a central nervous system (CNS)-active, third generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations, with demonstrated efficacy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). We present the rationale and design for TARGET (NCT05526755), which will evaluate the efficacy and safety of 5 years of adjuvant osimertinib in patients with completely resected EGFRm stage II to IIIB NSCLC. Materials and MethodsTARGET is a phase II, multinational, open-label, single-arm study. Adults aged ≥18 years (Taiwan ≥20 years), with resected stage II to IIIB NSCLC are eligible; prior adjuvant chemotherapy is allowed. Eligible patients must have locally confirmed common (exon 19 deletion or L858R) or uncommon (G719X, L861Q, and/or S768I) EGFR-TKI sensitizing mutations, alone or in combination. Patients will receive osimertinib 80 mg once daily for 5 years or until disease recurrence, discontinuation or death. The primary endpoint is investigator-assessed disease-free survival (DFS) at 5 years (common EGFR mutations cohort). Secondary endpoints include: investigator-assessed DFS at 3 and 4 years; overall survival at 3, 4, and 5 years (common EGFR mutations cohort); DFS at 3, 4, and 5 years (uncommon EGFR mutations cohort); safety and tolerability, type of recurrence and CNS metastases (both cohorts). Exploratory endpoints include: tissue/plasma concordance; analysis of circulating molecules in plasma samples using different profiling approaches to detect minimal residual disease; incidence and change over time of incidental pulmonary nodules. ResultsTARGET is currently recruiting, and completion is expected in 2029.

Traitement standard des stades III non résécables: Standard therapy for unresectable Stage III Non-Small Cell Lung Cancer

Approximately 25% of Non-small Cell Lung Cancer (NSCLC) present with a locally advanced disease. Stage III NSCLC includes heterogeneous diseases in term of initial clinical presentation and therapeutic strategy. An optimal initial staging integrating a PET/CT, EBUS mediastinal nodes exploration and an injected brain imaging is necessary. Pulmonary function test is to be systematically realized. The therapeutic strategy is decided in a multidisciplinary tumor board by an experimented team. Most of the stage IIIB and IIIC NSCLC receive a radio-chemotherapy. A concurrent plan is to be favored to a sequential plan. Platinum doublets comprise most standard chemotherapy regimens and must be started as early as possible. For fail or elderly patients who could not benefit from a concurrent chemotherapy, a sequential normo-fractionnated radiotherapy, or even a single chemotherapy are possible alternatives. After radio-chemotherapy, a consolidation systemic treatment by durvalumab, a checkpoint inhibitor, is currently a standard of care, in patients with a PD-L1 expressing tumor, based on the PACIFIC trial overall survival results.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Randomized, open-label phase II study of brigatinib and carboplatin plus pemetrexed and brigatinib alone for chemotherapy-naive patients with ALK-rearranged non-squamous non-small cell lung cancer: treatment rationale and protocol design of the B-DASH study (WJOG 14720 L)

BackgroundThe ALTA-1L study compared brigatinib with crizotinib in untreated ALK-rearranged non-small cell lung cancer (NSCLC) patients, demonstrating the efficacy of brigatinib. Although the median progression-free survival (PFS) of brigatinib group was 24.0 months, the one-year PFS rate was 70%. In the NEJ009 study, patients with EGFR mutations showed improved outcomes with gefitinib plus chemotherapy compared with gefitinib monotherapy. To evaluate the efficacy of the combination of brigatinib with chemotherapy for patients with ALK-rearranged NSCLC, we designed B-DASH study (WJOG 14720L).MethodsB-DASH study is a multicenter, two-arm, phase II study. Eligible patients have untreated stage IIIB, stage IIIC, stage IV, or postoperative relapse ALK-rearranged nonsquamous NSCLC. Patients will be randomized in a 1:1 ratio to receive brigatinib (180 mg once daily with a 7-day lead-in period at 90 mg) monotherapy or carboplatin (area under the curve = 5 on day 1) plus pemetrexed (500 mg/m2 on day 1) and brigatinib in a 3-week cycle for up to four cycles, followed by pemetrexed and brigatinib as maintenance therapy. The target hazard ratio of 0.62 is set based on the NEJ009 study. With one-sided alpha = 0.20 and power = 0.8, the sample size for the B-DASH study was calculated to be 110, considering the possibility of patients dropping out. The primary endpoint is PFS. The key secondary endpoints are the overall response rate and overall survival. We will evaluate tumor-derived DNA from plasma specimens before treatment, 42 days after administering the study drug, and on the day of progressive disease. Recruitment began in November 2021 and is ongoing.DiscussionThe efficacy of combination therapy with tyrosine kinase inhibitors and cytotoxic chemotherapy was demonstrated in patients with EGFR mutations but remains unclear in patients with ALK-rearranged NSCLC. The B-DASH study is the only trial of brigatinib combined with chemotherapy in patients with untreated ALK-rearranged NSCLC.Trial registrationjRCT identifier: jRCTs041210103.

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.

Neoadjuvant Camrelizumab Plus Platinum-Based Chemotherapy vs Chemotherapy Alone for Chinese Patients With Resectable Stage IIIA or IIIB (T3N2) Non–Small Cell Lung Cancer

The benefit of neoadjuvant camrelizumab plus chemotherapy for resectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) remains unknown. To assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy vs chemotherapy alone for patients with resectable stage IIIA or IIIB NSCLC. In this randomized phase 2 clinical trial conducted at 2 hospitals in China, patients aged 18 to 70 years with resectable stage IIIA or IIIB (T3N2) NSCLC were enrolled between April 7, 2020, and January 12, 2022. Patients were randomly assigned to receive 3 cycles of camrelizumab (200 mg) plus chemotherapy (nab-paclitaxel, 130 mg/m2, and platinum [cisplatin, 75 mg/m2; carboplatin, area under the curve, 5; or nedaplatin, 100 mg/m2]) or chemotherapy alone, followed by surgery after 4 to 6 weeks. The primary end point was the pathologic complete response (pCR) rate. Secondary end points included the major pathologic response (MPR) rate, objective response rate (ORR), event-free survival (EFS), and safety. Disease-free survival (DFS, defined as the time from surgery to disease recurrence or death from any cause) was analyzed post hoc. Efficacy was assessed on a modified intention-to-treat basis. Ninety-four Chinese patients were randomized, and 88 (93.6%; median age, 61 years [IQR, 54-65 years]; 74 men [84.1%]) received allocated neoadjuvant treatment (43 received camrelizumab plus chemotherapy, and 45 received chemotherapy alone). Among these 88 patients, the pCR rate was 32.6% (14 of 43; 95% CI, 19.1%-48.5%) with camrelizumab plus chemotherapy vs 8.9% (4 of 45; 95% CI, 2.5%-21.2%) with chemotherapy alone (odds ratio, 4.95; 95% CI, 1.35-22.37; P = .008). The MPR rates were 65.1% (95% CI, 49.1%-79.0%) with camrelizumab plus chemotherapy and 15.6% (95% CI, 6.5%-29.5%) with chemotherapy alone. The radiographic ORRs were 72.1% (95% CI, 56.3%-84.7%) with camrelizumab plus chemotherapy and 53.3% (95% CI, 37.9%-68.3%) with chemotherapy alone. With a median follow-up of 14.1 months (IQR, 9.2-20.9 months), the median EFS and DFS were not reached in either group. The most common neoadjuvant treatment-related adverse events of grade 3 or higher were decreased white blood cell count (6 of 43 [14.0%] in the camrelizumab plus chemotherapy group vs 2 of 45 [4.4%] in the chemotherapy group) and decreased neutrophil count (3 of 43 [7.0%] in the camrelizumab plus chemotherapy group vs 5 of 45 [11.1%] in the chemotherapy group). No treatment-related deaths were reported. This randomized clinical trial found that among patients with resectable stage IIIA or IIIB (T3N2) NSCLC, camrelizumab plus chemotherapy, compared with chemotherapy alone, significantly improved the pCR rate with manageable toxic effects. ClinicalTrials.gov Identifier: NCT04338620.

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.

Safety and efficacy of two-drug combination in elderly patients with locally advanced non-small cell lung cancer and validation of the Charlson Index as a predictor of survival.

The best platinum-based chemotherapy regimen remains to be determined in elderly patients treated with definitive chemoradiotherapy for advanced non-small cell lung cancer (NSCLC). Predictive indexes for toxicity and survival are also needed to give the safest and most effective treatment for this population. This is a retrospective cohort study. Patients with histologically confirmed stage IIIA, IIIB or IIIC NSCLC over 70 years of age, treated with radiotherapy and chemotherapy, were included. Patients from two cancer centers treated between 12/2006 and 08/2019 were included in the data analysis. Fifty-eight patients were enrolled in the study. The median age was 76.6 years [interquartile range (IQR): 71.6-83.4]. Thirty-nine patients were treated with concomitant chemoradiotherapy and 19 with a sequential strategy. The chemotherapy regimen consisted in a combination of platinum and taxanes. At a median follow-up of 52 months (IQR: 7-69), the 2-year progression-free survival (PFS) and overall survival (OS) were 35.5% and 66.9%, respectively. Male sex and a high Charlson index were identified as independent prognostic factors for worse OS. Acute grade 3-5 toxicities occurred in 34.4% of patients, including 1 grade 5 toxicity, and grade 3-4 late toxicities occurred in 17.2% of patients. In the whole cohort a high Charlson index was the only predictive factor for a higher risk of grade 3-5 acute toxicities (statistical trend in the concurrent cohort, P=0.06). The Charlson index correlated with toxicity and survival in elderly patients treated with chemoradiotherapy in locally advanced NSCLC. The addition of taxanes to platinum chemotherapy was safe in the present study and warrants further exploration.

Perioperative Nivolumab and Chemotherapy in Stage III Non–Small-Cell Lung Cancer

BackgroundApproximately 20% of patients with non–small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients.MethodsIn this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety.ResultsA total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P=0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan–Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan–Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%).ConclusionsIn patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.)

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 .