Unresectable Non-small Cell Lung Cancer Research Articles

Draw on advantages and avoid disadvantages: CT-derived individualized radiomic signature for predicting chemo-radiotherapy sensitivity in unresectable advanced non-small cell lung cancer

BackgroundPresently, the options of concurrent chemo-radiotherapy (CCR) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) are controversial and there is no reliable prediction tool to stratify poor- and good-responders. Although radiomic analysis has provided new opportunities for personalized medicine in oncological practice, the repeatability and reproducibility of radiomic features are critical challenges that hinder their widespread clinical adoption. This study aimed to develop a qualitative radiomic signature based on the within-sample rank of radiomics features, and to use this novel method to predict CCR sensitivity in LA-NSCLC, avoiding the variability of quantitative signatures to multicenter effect.MethodsWe retrospectively analyzed 125 patients with stage III NSCLC who received treatment from our hospital. Radiomic features were extracted from pretreatment plain CT scans and constructed as feature pairs based on their within-sample rank. Fisher and univariate Cox analyses were performed to select feature pairs significantly associated with patients’ overall survival (OS). NSCLC-Radiomic (R422) cohort including 104 NSCLC patients was used as an independent testing cohort. NSCLC-Radiogenomic (RG211) cohort with matched RNA sequencing profiles, was used for functional enrichment analysis to reveal the underlying biological mechanism reflected by the signature.ResultsA qualitative signature, consisting of 15 radiomic feature pairs (termed as 15-RiFPS), was developed based on the Genetic Algorithm, which could optimally distinguish responder from non-responder with significantly improved OS if they received CCR treatment (log-rank P = 0.0009, HR = 13.79, 95% CIs 1.83–104.1). The performance of 15-RiFPS was validated in an independent public cohort (log-rank P = 0.0037, HR = 2.40, 95% CIs 1.30–4.40). Furthermore, the transcriptomic analyses provided biological pathways (‘glutathione metabolic process’, ‘cellular oxidant detoxification’) underlying the signature.ConclusionsWe developed a CT-derived 15-RiFPS, which could potentially help predict individualized therapeutic benefit of CCR in patients with LA-NSCLC. Additionally, we investigated the underlying intra-tumoral biological characteristics behind 15-RiFPS which would accelerate its clinical application. This approach could be applied to a wider range of treatments and cancer types.

Expectations concerning cancer treatment: perspectives of medical oncologists and patients on advanced, unresectable lung carcinoma.

This study seeks to compare expectations regarding systemic cancer treatment for advanced lung cancer from the perspectives of both patient and medical oncologist. A cross-sectional study involving 17 medical oncologists from 13 Spanish hospitals between 2021 and 2022. Patients with advanced, unresectable lung cancer were recruited prior to initiating systemic cancer treatment. Both patients and oncologists completed the NEOetic-EIT and the STAR. Seventeen medical oncologists specializing in lung cancer participated, with a mean age of 36.2 years (range 28-56); 65% were female. The study included 298 patients with advanced, unresectable lung cancer, predominantly non-small cell type (72%), and most at stage IV (77%). Most patients were retired or unemployed (71%), and married or partnered (77%). Treatment approaches varied, with 44% based on biomarkers. Oncologists had greater expectations of positive outcomes for participants with better baseline prognosis, such as ECOG 0, newly diagnosed, locally advanced, unresectable non-small cell lung cancer, and those receiving biomarker-based treatments. In contrast, patients' treatment expectations did not vary based on sociodemographic or clinical factors. Generally, patients had high expectations of cure, in contrast to oncologists' lower expectations, though both anticipated similar quality-of-life improvements. Patients anticipated more side effects than oncologists. Among oncologists, expectations varied by gender and decreased with age and experience, with no differences detected among patients based on gender, age, or doctor-patient relationship. This study reveals the complex expectations of patients and oncologists in advanced lung cancer treatment. It underscores the need for effective communication in oncology to align patient expectations with clinical realities.

Evaluation of Radiation Pneumonitis in a Phase II Study of Consolidation Immunotherapy with Nivolumab and Ipilimumab or Nivolumab Alone Following Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-Small Cell Lung Cancer (NSCLC): Big Ten Cancer Research Consortium BTCRC-LUN16-081

Purpose/Objective(s)The addition of immunotherapy (IO) after concurrent chemoradiation (CCRT) for unresectable non-small cell lung cancer (NSCLC) has become common practice in eligible patients. Approaches to further improve outcomes and reduce treatment-related toxicity for these patients are needed. This study evaluates the risk of radiation pneumonitis after CCRT and its correlation with the radiation dose distribution, immunotherapy regimen (nivolumab vs nivolumab plus ipilimumab), and patient demographics across BTCRC-LUN16-081. Materials/MethodsPatients with unresectable stage III NSCLC after completion of CCRT were enrolled on BTCRC-LUN16-081, a randomized phase II trial to assess efficacy and tolerability of consolidative nivolumab versus nivolumab plus ipilimumab for six months. Radiation dose parameters, patient demographics, and toxicity events were evaluated among treatment arms for risk and severity of pneumonitis. ResultsOne-hundred and five patients were enrolled into two treatment arms, 54 patients received nivolumab alone and 51 patients received nivolumab plus ipilimumab. Of these, 104 patients had dose volume histogram (DVH) information available. Within this cohort, 65 patients (62.5%) had stage IIIA and 39 patients (37.5%) had stage IIIB NSCLC disease per AJCC 7th edition. During the study, 29 patients (27.9%) were diagnosed with grade 2 or greater pneumonitis. Utilizing logistic regression and evaluating different cut-offs for lung V20, patients with V20 >23% demonstrated significantly higher grade 2 or greater pneumonitis rates (37.1% vs. 16.2%, P = .031). No significant difference in rates of pneumonitis between arms were identified. Traditional lung DVH cut-offs (V5 of >65%, V20 of >35%, mean >20 Gy) were not associated with pneumonitis. ConclusionIn patients receiving nivolumab or nivolumab plus ipilimumab after definitive CCRT, lung V20 of >23% was associated with an increased risk of grade 2 or greater pneumonitis. Radiation dose constraints for lungs in patients receiving consolidative IO after CCRT should continue to be evaluated and optimized when feasible.

Safety and Efficacy of Durvalumab After Chemoradiotherapy in Antinuclear Antibody-positive Patients With Non-small Cell Lung Cancer.

Pneumonitis during durvalumab consolidation therapy after chemoradiotherapy (CRT) is a major cause of treatment discontinuation. Although previous studies have revealed an association between antinuclear antibody (ANA) positivity and the safety and efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC), there are no reports on durvalumab consolidation therapy. This study investigated the safety and efficacy of durvalumab after CRT in ANA-positive patients. We retrospectively reviewed patients with unresectable NSCLC treated with durvalumab after CRT between August 2018 and July 2022 at our institution. We evaluated the association among ANA positivity, treatment-related adverse events (AEs), and survival outcomes. Overall, 80 patients were enrolled, 39 of whom were ANA-positive. Although there were no significant differences in the incidence of each AE of any grade, ANA-positive patients tended to have a higher frequency of pneumonitis of grade 3 to 5 than ANA-negative patients (12.8% vs. 2.4%, p=0.104). ANA-positive patients had a significantly shorter median progression-free survival (PFS) and overall survival (OS) than ANA-negative patients [14.9 months vs. not reached (NR), p=0.005; NR vs. NR, p=0.013]. Multivariate analysis revealed that ANA positivity was an independent predictor of shorter PFS (HR=2.23; 95% CI=1.16-4.29; p=0.016) and OS (HR=2.28; 95% CI=1.01-5.12; p=0.046). ANA-positive patients receiving durvalumab after CRT tended to have a higher frequency of severe pneumonitis and significantly worse PFS and OS compared with ANA-negative patients.

A phase III study to access the safety and efficacy of prolgolimab 250 mg fixed dose administered every 3 weeks versus prolgolimab 1 mg/kg every 2 weeks in patients with metastatic melanoma (FLAT).

Prolgolimab is the first Russian PD-1 inhibitor approved for the first-line treatment of unresectable or metastatic melanoma and advanced non-small cell lung cancer. It was approved in two weight-based regimens of 1 mg/kg Q2W and 3 mg/kg Q3W, but because of re-evaluation of weight-based dosing paradigm, studying of a fixed-dose regimen was considered perspective. We conducted a multicenter, single-arm, open-label efficacy, pharmacokinetics, and safety study to obtain data that would allow the approval of the new flat dosing regimen of prolgolimab in patients with previously untreated unresectable or metastatic melanoma (BCD-100-8/FLAT, NCT05783882). The primary objective was to prove the non-inferiority of prolgolimab 250 mg Q3W versus prolgolimab 1 mg/kg Q2W for the treatment of patients with unresectable or metastatic melanoma in terms of ORR according to RECIST 1.1. Patients from the MIRACULUM study (BCD-100-2/MIRACULUM, NCT03269565) comprised a historical control group. One hundred fourteen patients received prolgolimab 250 mg Q3W, and 61 patients received prolgolimab (Prolgo) 1 mg/kg Q2W (historical control). Objective response was achieved by 33.3% [95% confidence interval (CI): 24.8, 42.8] of patients in the Prolgo 250 mg group compared with 32.8% (95% CI: 21.3, 46.0) of patients in the Prolgo 1 mg/kg group. Risk difference was 0.00, 95% CI (-0.12; NA), p = 0.0082. Both regimens were well tolerated, and safety profiles were comparable. The pharmacokinetic analysis (PK) showed that the regimen with the fixed dose of 250 mg Q3W was characterized by higher PK parameters. The immunogenicity study did not detect binding antibodies to prolgolimab in any of the subjects. The obtained results showed that the selected fixed dosing regimen of prolgolimab 250 mg Q3W is characterized by efficacy and safety parameters comparable to that observed for the 1 mg/kg Q2W regimen.

Characteristics and outcomes of salvage surgery after immune checkpoint inhibitor therapy for initially unresectable non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) improved the long-term survival outcomes in patients with advanced non-small cell lung cancer (NSCLC), whereas the role of salvage surgery after ICIs was unknown. The object of this study was to investigate characteristics and outcomes of patients who underwent salvage surgery after ICIs. Retrospective chart review was performed on the basis of our multi-institutional database in search of consecutive patients who underwent salvage surgery after ICIs for initially unresectable NSCLC between 2016 and 2022. Patient characteristics, intraoperative findings, perioperative outcomes, histopathological findings, progression-free survival (PFS), and overall survival (OS) were investigated. Fifteen patients with a median age of 71 years were included in the study. The surgical approach was open thoracotomy in 5 and robotic or thoracoscopic surgery in 10 patients. Resection was performed for primary lesions in 8 and metastatic lesions in 7 patients. Postoperative complication was noted in 1 patient with grade 1 phrenic nerve palsy. The median PFS was 47.9 months, and the median OS was not reached. Three-year PFS was 0% in those with metastatic lesions and 87.5% in those with primary lesions (P=0.12). Salvage surgery after ICIs may be associated with low perioperative morbidity and acceptable long-term outcomes in selected patients. Salvage resection of primary lesions may be associated with more favorable PFS than of metastatic lesions.

FDA approval summary: fam-trastuzumab deruxtecan-nxki for unresectable or metastatic non-small cell lung cancer with activating HER2 mutations.

On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥ 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.

Therapeutic effect of induction therapy including nab-paclitaxel followed by surgical resection for the patients with locally advanced non-small-cell lung cancer

BackgroundLung cancer is associated with a high mortality rate worldwide. Non-small-cell lung cancer (NSCLC) is a major subtype of lung cancer. Carboplatin (CBDCA) plus nab-paclitaxel (PTX) has become a standard treatment for advanced unresectable NSCLC. However, treatment with nab-PTX has not been established as a standard therapy for resectable locally advanced (LA)-NSCLC.MethodsWe conducted a comprehensive study involving consecutive patients with locally advanced NSCLC who underwent induction therapy including nab-PTX followed by surgical resection. Fifteen patients with locally advanced NSCLC underwent induction therapy including nab-PTX followed by surgical resection. Concurrent chemoradiotherapy (CRT) consisted of weekly administration of nab-PTX (50 mg/m2) plus CBDCA (area under the plasma concentration time curve (AUC) 2) and thoracic radiotherapy (50 Gy/25 fractions).ResultsThe clinical stages were as follows: IIB (n =1), IIIA (n =12), and IIIC (n =2). Downstaging was observed in 73% (11/15) of patients on comparison with the clinical stage before concurrent CRT. Adverse drug reactions were observed in seven patients. Complete resection was performed in all patients. The re-evaluated pathological stage after pretreatment was diagnosed as stage 0 in three patients, stage IA1 in six, stage IA2 in one, and stage IIIA in five. The pathological effects of previous therapy were as follows: Ef3 (n =3), Ef2 (n =9), and Ef1a (n =3).ConclusionThe therapeutic effect of induction therapy including nab-PTX was promising. Induction CRT, including nab-PTX, followed by resection, may be a viable alternative treatment option for locally advanced NSCLC.

Real-World Treatment Patterns and Clinical Outcomes Among Patients with Metastatic or Unresectable EGFR-Mutated Non-Small Cell Lung Cancer Previously Treated with Osimertinib and Platinum-Based Chemotherapy.

For patients with epidermal growth factor receptor-mutated (EGFRm) locally advanced/metastatic non-small cell lung cancer (mNSCLC) whose disease has progressed on or after osimertinib and platinum-based chemotherapy (PBC), no uniformly accepted standard of care exists. Moreover, limited efficacy of standard treatments indicates an unmet medical need, which is being addressed by ongoing clinical investigations, including the HERTHENA-Lung01 (NCT04619004) study of patritumab deruxtecan (HER3‑DXd). However, because limited information is available on real-world clinical outcomes in such patients, early-phase trials of investigational therapies lack sufficient context for comparison. This study describes the real-world clinical characteristics, treatments, and outcomes for patients with EGFRm mNSCLC who initiated a new line of therapy following previous osimertinib and PBC, including a subset matched to the HERTHENA-Lung01 population. This retrospective analysis used a US database derived from deidentified electronic health records. The reference cohort included patients with EGFRm mNSCLC who had initiated a new line of therapy between November 13, 2015 and June 30, 2021, following prior osimertinib and PBC. A subset of patients resembling the HERTHENA-Lung01 population was then extracted from the reference cohort; this matched subset was optimized using propensity score (PS) weighting. Endpoints were real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). Confirmed real-world objective response rate (rwORR; partial/complete response confirmed ≥ 28days later) was calculated for the response-evaluable subgroups of patients (with ≥ 2 response assessments spaced ≥ 28days apart). In the reference cohort (N = 273), multiple treatment regimens were used, and none was predominant. Median rwPFS and rwOS were 3.3 and 8.6months, respectively; confirmed rwORR (response evaluable, n = 123) was 13.0%. In the matched subset (n = 126), after PS weighting, median rwPFS and rwOS were 4.2 and 9.1months, respectively; confirmed rwORR (response evaluable, n = 57) was 14.1%. The treatment landscape for this heavily pretreated population of patients with EGFRm mNSCLC is fragmented, with no uniformly accepted standard of care. A high unmet need exists for therapeutic options that provide meaningful improvements in clinical benefit.

A Pilot Trial of Proton-Based Cardiac Sparing Accelerated Fractionated Radiation Therapy in Unresectable Non-small Cell Lung Cancer With Extended Durvalumab Therapy (PARTICLE-D)

Purpose: Concurrent chemoradiotherapy is the current non-surgical standard of care for locally advanced non-small cell lung cancer (NSCLC). However, this is a difficult regimen to tolerate especially for those who are elderly, have multiple comorbidities or poor performance status. Alternative treatment regimens are needed for this vulnerable population. We report initial results of concurrent durvalumab, an immune checkpoint inhibitor, and hypofractionated, dose-escalating, proton external beam radiotherapy (EBRT).Patients and Methods: This phase I, pilot dose-escalation trial enrolled seven patients with newly diagnosed stage IIIA-IIIC NSCLC who were unable or unwilling to undergo concurrent chemoradiotherapy. Patients previously treated with immunotherapy were excluded. Five patients in the initial phase of this 3+3 study design received a fixed dose of durvalumab each 28-day cycle plus hypofractionated proton EBRT 60 Gy in 20 fractions while two patients received the escalation dose of 69 Gy in 23 fractions. The primary objective assessed safety while secondary objectives assessed feasibility and adverse events.Results: All patients experienced treatment-related adverse events, primarily grades 1-2. Pneumonitis and anemia were the most common. Only one dose limiting toxicity occurred, in arm one, which was a grade 3 pneumonitis leading to grade 5 pneumonia. Additionally, two delayed-onset grade 5 tracheal necrosis events occurred > 13 months after treatment initiation.Conclusions: Concurrent durvalumab plus hypofractionated proton EBRT was well tolerated in the short term. However, three treatment-related deaths, including two delayed-onset grade 5 tracheal necroses negatively impacted overall safety. A dose de-escalation protocol of proton-based radiotherapy plus durvalumab is warranted.

PD-L1 expression from surgically resected lung tumors predictive of early progression in patients previously treated with targeted therapy for initially unresectable non-small cell lung cancer.

Recent evidences showed that resection of lung tumor post-targeted therapy has shown progression-free survival (PFS) benefits in initially unresectable patients. The aim of this study is to evaluate pathologic findings of resected lung tumor samples in patients who have undergone prior epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) treatment, and also to assess the prognostic factors related to outcomes after resection. The deidentified data of non-small cell lung cancer (NSCLC) patients admitted to seven university hospitals affiliated with the Catholic University of Korea were obtained from the Clinical Data Warehouse (CDW) database. Among screened patients, 40 individuals who had previously undergone targeted therapies and later received surgical resection of a primary lung tumor were evaluated for the study. All 40 patients were diagnosed with adenocarcinoma. Of these, 36 with EGFR mutations received prior EGFR TKI treatment. Only one postoperative complication, atrial fibrillation, was observed. At the time of resection, 19 patients showed primary lung tumor size regressing or unchanged, while 21 patients showed primary lung tumor regrowth or new lesions being developed before the resection. The group with no programmed death-ligand 1 (PD-L1) expression from resected samples showed significantly better post-resection PFS when compared to the other group (P=0.01). In the Model II multivariate analysis for post-resection PFS, PD-L1 detection from the resected sample was significantly associated with PFS [P=0.03; hazard ratio (HR) =5.465; 95% confidence interval (CI): 1.200-24.885]. Furthermore, an increase in PD-L1 expression compared to the baseline value was associated with an increasing lung tumor burden at the time of resection (P=0.03). Resected specimen following targeted therapy can provide valuable clinical information that can be used to predict the prognosis of patients with initially unresectable NSCLC.

PPD01.09 Cardiac Events following Concurrent Chemotherapy and Radiation with Durvalumab Consolidation for Unresectable Non-metastatic Non-Small Cell Lung Cancer

PPD01.09 Cardiac Events following Concurrent Chemotherapy and Radiation with Durvalumab Consolidation for Unresectable Non-metastatic Non-Small Cell Lung Cancer

Phase II Trial Assessing Toxicity of Personalized Response-Based Radiation Treatment in Patients with Locally Advanced Non-Small Cell Lung Cancer

IntroductionLocal failure rates after treatment for locally advanced non-small-cell lung cancer (NSCLC) remain high. Efforts to improve local control with uniform dose-escalation or dose-escalation to mid-treatment PET-avid residual disease have been limited by heightened toxicity. This trial aimed to refine response-based adaptive radiation (RT) and minimize toxicity by incorporating FDG-PET and V/Q SPECT imaging mid-treatment. Methods47 patients with Stage IIA-III unresectable NSCLC were prospectively enrolled in this single-institution trial (NCT02492867). Patients received concurrent chemoradiation with personalized response-based adaptive RT over 30 fractions incorporating V/Q SPECT and FDG-PET. The first 21 fractions (46.2Gy at 2.2 Gy/fraction) were delivered to the tumor while minimizing dose to SPECT-defined functional lung. The plan was then adapted for the final 9 fractions (2.2-3.8Gy/fraction) up to a total of 80.4Gy, based on mid-treatment FDG-PET tumor response to escalate dose to residual tumor while minimizing dose to SPECT-defined functional lung. Non-progressing patients received consolidative carboplatin/paclitaxel or durvalumab. The primary endpoint of the study was ≥ grade 2 lung and esophageal toxicities. Secondary endpoints included time to local progression, tumor response, and overall survival. ResultsAt one year post-treatment, the rates of grade 2 and grade 3 pneumonitis were 21.3% and 2.1%, respectively, with no difference in pneumonitis rates among patients who received and did not receive adjuvant durvalumab (p=0.74). While there were no grade 3 esophageal-related toxicities, 66.0% of patients experienced grade 2 esophagitis. 1- and 2-year local control rates were 94.5% (95% CI, 87.4% - 100%) and 87.5% (95% CI, 76.7% - 100%), respectively. Overall survival was 82.8% (95% CI, 72.6% -94.4%) at 1 year and 62.3% (95% CI, 49.6%-78.3%) at 2 years. ConclusionsResponse-based adaptive dose-escalation accounting for tumor change and normal tissue function during treatment provided excellent local control, comparable toxicity to standard chemoradiation, and did not increase toxicity with adjuvant immunotherapy.

Evolving Precision First-Line Systemic Treatment for Patients with Unresectable Non-Small Cell Lung Cancer.

First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades. First, molecularly targeted therapy for a growing number of gain-of-function molecular targets has been shown to improve progression-free survival (PFS) and overall survival (OS) with favorable toxicity profiles compared to platinum-containing chemotherapy and can be given as first-line systemic therapy in ~25% of patients with NSCLC. Actionable genetic alterations include EGFR, BRAF V600E, and MET exon 14 splicing site-sensitizing mutations, as well as ALK-, ROS1-, RET-, and NTRK-gene fusions. Secondly, inhibitors of programmed cell death protein 1 or its ligand 1 (PD-1/L1) such as pembrolizumab, atezolizumab, or cemiplimab monotherapy have become a standard of care for ~25% of patients with NSCLC whose tumors have high PD-L1 expression (total proportion score (TPS) ≥50%) and no sensitizing EGFR/ALK alterations. Lastly, for the remaining ~50% of patients who are fit and whose tumors have no or low PD-L1 expression (TPS of 0-49%) and no sensitizing EGFR/ALK aberrations, platinum-containing chemotherapy with the addition of a PD-1/L1 inhibitor alone or in combination of a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor improves PFS and OS compared to chemotherapy alone. The objectives of this review are to summarize the current data and perspectives on first-line systemic treatment in patients with unresectable NSCLC and propose a practical algorithm for implementing precision biomarker testing at diagnosis.

Predictive value of primary tumor volume change during concurrent chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer

Background and purposeNo established early biomarkers currently exist to predict responses during concurrent chemoradiotherapy (CCRT) in patients with unresectable non-small cell lung cancer (NSCLC). This study investigated the potential of gross tumor volume (GTV) and its changes during CCRT as predictors of survival outcomes. Materials and methodsWe identified 227 patients with unresectable stage III NSCLC who underwent definitive CCRT followed by durvalumab between November 2018 and December 2022. GTV was defined as the volume of the primary tumor, assessed at two time points: before starting CCRT for initial planning (GTV1), and at the fourth week of CCRT for adaptive planning (GTV2). Both relative and absolute regressions between GTV1 and GTV2 were calculated. ResultsThe median GTV1 volume was 90 mL (range, 5–840 mL), and the median GTV2 volume was 64 mL (range, 1–520 mL), resulting in median absolute and relative regressions of 18.6 mL and 25.0 %, respectively. Among the GTV parameters, relative GTV regression exhibited the strongest predictive value, with an area under the curve (AUC) of 0.804 for in-field progression and 0.711 for overall progression. The 1-year progression-free survival rates for the high (>30 %), intermediate (0–30 %), and low (≤0%) relative regression groups were 88.0 %, 62.6 %, and 14.3 %, respectively (p = 0.006 for high vs. intermediate; p < 0.001 for intermediate vs. low). Additionally, GTV2 volume demonstrated stronger associations with survival outcomes than GTV1 volume. ConclusionRelative GTV regression was identified as a promising early predictor for patients with unresectable stage III NSCLC. Further development of a multi-parametric predictive model is warranted to guide patient-tailored therapeutic approaches.

Induction therapy with PD-1 antibody combined with platinum-based doublet chemotherapy for locally-advanced non-small cell lung cancer: A randomised controlled, open-label, phase 2 trial.

8044 Background: Chemoradiotherpay plus immunotherapy is recommended for unresectable locally-advanced non-small cell lung cancer (NSCLC) based on PACIFIC trial. However, it is unclear whether surgery can provide survival benefit for patients with tumors initially unresectable transformed into resectable ones after chemoimmunotherapy. This trial aims to investigate the efficacy and safety of the therapeutic regimen of chemoimmunotherapy plus surgery or radiotherapy. Methods: Patients with unresectable stage IIIB-IIIC NSCLC were enrolled to receive 4 cycles (q21d) of PD-1 antibody (Serplulimab, 4.5mg/kg) and platinum-based doublet chemotherapy. After the induction therapy, those with disease downstaged to IIIA or lower stage and resectable were randomized to receive radical surgery or radiotherapy with a ratio of 1:1, and those with stage IIIB or higher stage or unresectable disease after induction therapy were then treated by oncologists. Primary endpoint was event-free survival (EFS). Secondary endpoints included objective response rate (ORR), major pathologic response (MPR), pathologic complete response (pCR), progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), R0 rate of resection, severe adverse event (SAE) rate, and health related quality of life (HRQol). Preliminary short-term results were collected. Results: One hundred patients will be enrolled as planned, and a total of 82 patients were enrolled by the data cutoff date (January 6, 2024). Fifty-four and 28 patients were diagnosed with stage IIIB and IIIC disease, respectively. The percentage of squamous carcinomas, adenocarcinomas, and NSCLCs not otherwise specified were 68.3% (56/82), 15.9% (13/82), and 15.9% (13/82), respectively. ORR in 73 evaluable patients was 74.0% (54/73). Twenty-six of them are still in induction therapy phase, and the other 47 and 9 patients received 4 cycles and 1-3 cycles of induction therapy, respectively. Thirty-one patients had downstaged and resectable disease after 4 cycles of induction therapy, and 26 of them were randomized to arm A (n = 13) and arm B (n = 13), and 5 refused randomization (3 received surgery). One patient received surgery after 2 cycles of induction therapy. In 56 patients finished 1-4 cycles of induction therapy, the rate of conversion to resectability was 57.1% (32/56). In total, 17 patients received surgery, and the MPR and pCR rate in 16 evaluable patients were 62.5% (10/16) and 31.3% (5/16), respectively. The grade 3-5 adverse event rate in 56 patients finished induction therapy was 50.0% (28/56). One patient died of immune-related pneumonia. Conclusions: Induction therapy with PD-1 antibody (Serplulimab) and chemotherapy could transform half of unresectable stage IIIB-IIIC NSCLC into resectable, and the efficacy and safety were satisfactory. Clinical trial information: NCT05766800 .

Phase II study of induction platinum doublet in combination with nivolumab followed by surgery or concurrent chemotherapy-nivolumab-radiation in unresectable stage IIIA-C non-small cell lung cancer (NSCLC).

TPS8122 Background: For patients (pts) with stage IIIA-IIIC NSCLC, though standard of care chemo-radiation (XRT) followed by 1 year of durvalumab has improved 5 year overall survival (OS), fewer than 50% survive 5 years. In this study, we adopted the established neoadjuvant chemotherapy (chemo) plus nivolumab (nivo) CheckMate-816 regimens for resectable stage I(&gt;4cm)-IIIA yielding an increased complete pathologic response (pCR) rate and event free survival compared to chemo alone, as induction therapy in unresectable stage IIIA-IIIC NSCLC. The intent is to use induction chemo-nivo to treat pts traditionally considered unresectable (multi-station N2 or N3 disease) in order to downstage them enough to permit surgical resection. The study is structured to change (1) the immune checkpoint inhibitor (ICI) regimen to induction rather than consolidation which enables the chance to observe the systemic therapy’s efficacy, treat micro-metastatic disease earlier, and may decrease the morbidity of the ablative therapies (2) the ICI containing regimen by increasing from single agent ICI to combination chemo plus nivo which may improve systemic efficacy (3) the duration of treatment with pre and post ablative ICI containing therapy.Induction also provides a platform for studying tumor biology with the chance to discover surrogate markers of response and resistance to the induction regimen matched against response ahead of the definitive therapy. Methods: This is an investigator initiated trial for pts with newly diagnosed clinical stage IIIA-IIIC EGFR/ALK/ROS1 WT, SQ and NSQ NSCLC with PS 0-1. Pts must be able to tolerate surgery and have a primary tumor which is technically resectable with an N stage IIIA &gt; 2 or more lymph node (LN) stations positive. Pts are treated with the same platinum doublet plus nivo regimens used in CheckMate-816 for 3 cycles followed by repeat CT and repeat biopsy of all LN stations biopsied at baseline and LN stations which at baseline had a high suspicion of harboring disease and which look technically unresectable. If the cancer is down-staged to a single LN station-N2, or is N1 or N0, the pt is offered surgery with an option of post-operative XRT. If not sufficiently down-staged, pts are treated with definitive chemo-nivo-XRT. All pts receive 1 year of consolidation nivo. The primary outcome is response to the induction regimen by repeat CT scan. Secondary outcomes include the rate of converting non-surgical stage III(A-C) to surgically resectable disease, pCR rate, extent of post-induction XRT field decrease, 2-year progression free survival, OS, quality of life, and exploratory outcomes include markers of resistance and response, and remote symptom monitoring. Enrolment will be 37 pts. The study is accruing with a plan to open at a second site. Clinical trial information: NCT06003075 .

Updated results from COAST, a phase 2 study of durvalumab (D) ± oleclumab (O) or monalizumab (M) in patients (pts) with stage III unresectable non-small cell lung cancer (uNSCLC).

8046 Background: D consolidation after concurrent chemoradiotherapy (cCRT) improves survival in pts with uNSCLC. Rational immunotherapy combinations may further improve outcomes. As radiotherapy can induce expression of CD73, HLA-E (NKG2A ligand), and PD-L1 in tumor cells, all of which suppress antitumor immunity, there is a rationale for blockade of these immune checkpoints after cCRT. Interim results from COAST (NCT03822351), a global, open-label, Phase 2 study of D ± M (anti-NKG2A) or O (anti-CD73) as consolidation therapy in pts with Stage III uNSCLC, suggested improved progression free survival (PFS) with D+O and D+M vs D alone. We present updated efficacy and safety. Methods: Pts with histologically / cytologically documented Stage III uNSCLC and ECOG PS 0 / 1 with no progression after cCRT were randomized (1:1:1; stratified by histology) within 42 days post cCRT to receive D 1500 mg IV every 4 weeks (Q4W) for 12 months ± O 3000 mg IV Q2W for two cycles then Q4W or M 750 mg IV Q2W. Primary endpoint: objective response rate (ORR). Key secondary endpoints: safety, PFS, and overall survival (OS). Results: From Jan 2019 to Jul 2020, 186 of 189 randomized pts received treatment. Baseline characteristics were generally balanced across arms. As of Jul 18, 2023, median follow-up was 30.1 mo (range, 0.4–48.9). Of pts receiving D, D+O, and D+M, 69.7%, 44.1%, and 41.0% discontinued treatment (Tx), primarily due to progressive disease (42.4%, 18.7%, and 19.6%) or adverse events (AEs; 15.2%, 15.3%, and 14.8%). Median exposure was 7 cycles (range, 1–13) for D, and 13 (1–13) for D+O and D+M. ORR, PFS, and OS (39.6% maturity) are summarized in the Table. Tx-emergent AEs occurred in 98.5%, 96.6%, and 100% (Grade [G] 3/4: 34.8%, 33.9%, and 32.8%) of pts receiving D, D+O, or D+M, respectively; immune-mediated AEs (imAEs) occurred in 34.8%, 25.4%, and 34.4% (G 3/4: 3.0%, 0%, and 3.3%); and the AE of special interest pneumonitis occurred in 16.7%, 20.3%, and 18.0% (G 3/4: 0%, 0%, and 1.6%). Subgroup analyses and biomarker data will be presented. Conclusions: D+O and D+M increased ORR and prolonged PFS and OS vs D alone. Safety was similar across arms, with no new safety signals. Further investigation of D, D+O, and D+M in this population is ongoing in the Phase 3 PACIFIC-9 study (NCT05221840). Clinical trial information: NCT03822351 . [Table: see text]

Overall survival after treatment with CAN-2409 plus valacyclovir in combination with continued ICI in patients with stage III/IV NSCLC with an inadequate response to ICI.

8634 Background: Patients with unresectable non-small cell lung cancer (NSCLC) with an inadequate response to immune checkpoint inhibitors (ICI) have limited therapeutic options and expected median overall survival (mOS) of 11.6 to 14.5m (PMID: 35658002 ). The immunosuppressive tumor microenvironment and the lack of a specific T cell response underpin inadequate clinical response. CAN-2409 is a replication-defective adenovirus encoding the HSV-tk gene. Transduced cells activate orally delivered valacyclovir, resulting in immunogenic cell death, and in situ immunization against the patient’s tumor antigens, eliciting a specific immune response against the injected tumor and uninjected metastases. Methods: NCT04495153 is an open-label, phase 2 clinical trial of CAN-2409 + valacyclovir in combination with continued ICI in patients with non-resectable, stage III/IV NSCLC, refractory or resistant to anti-PD-(L)1. Patients were enrolled in 2 cohorts (C) depending on disease status at enrolment: C1, stable disease or C2, progressive disease. Two doses of CAN-2409 (5x1011vp) were given 5-7w apart via bronchoscopic or percutaneous injection into lung tumor, disease-positive lymph node, or peripheral metastasis, each followed by oral prodrug. Patients were assessed for safety, immunologic biomarkers, and OS. Results: As of 16Jan2024, 73 patients were treated (safety population: ≥1 dose of CAN-2409) and 44 were evaluable per protocol (received 2 doses of CAN-2409+ valacyclovir and 12-week CT scan). Baseline treated pt median age was 67 [43-88] yrs, 44% female, 68% on aPD(L)1 alone and 32% aPD(L)1 + pemetrexed regimen. We observed no dose-limiting toxicities or ≥grade 4 treatment-related AEs. mOS of the evaluable population was estimated as 22.0m (95% CI: 14.3m, NA; median follow up (mFU) time of 18.2m). In C2 (n = 38) mOS was 20.6 (mFU 19.2.m) and in C1 (n = 6) was N.A. (mFU 15.2m). mOS in the safety population (n = 73) was 14.3.m (mFU16.8m). 64% of evaluable patients had systemic clinical response with shrinkage of both injected and uninjected lesions. We found a significant correlation between increases in T cell populations after the second injection of CAN-2409 (circulating memory and effector memory CD4+ and CD8+T cells, CD4+ Ki67+IFNg+ and CD4+granzymeB+ T cells, CD8+granzymeB+Ki67+ T cells, T regulatory cells) and subsequent OS (R2 between 0.181 and 0.354 and p = 0.043 and 0.004). Conclusions: Experimental treatment with CAN-2409+valacyclovir in NSCLC pts following an inadequate response to ICI is well tolerated and results in the induction of a cytotoxic and memory circulating T cell response associated with shrinkage of injected and uninjected lesions and a raised tail of the survival curve. mOS of the evaluable population was estimated as 22.0m, markedly longer than the expected mOS of 11.6-14.5m. Clinical trial information: NCT04495153 .

Efficacy of immunotherapy retreatment in patients with non-small cell lung cancer receiving consolidative durvalumab.

8625 Background: The standard of care for patients with stage III, unresectable non-small cell lung cancer (NSCLC) is curative intent chemoradiation followed by durvalumab consolidation. However, most patients progress necessitating further treatment. Although immunotherapy (IO) is the cornerstone of treatment in advanced/metastatic disease, the benefit in patients who received prior durvalumab is unclear. Clinical trials excluded prior IO exposure and current guidelines do not provide specific recommendations. This study aims to characterize the efficacy of post-durvalumab IO treatment. Methods: This was a retrospective cohort study conducted at the University of North Carolina (UNC) Medical Center. Adult patients with unresectable NSCLC who received chemoradiation and consolidative durvalumab followed by subsequent systemic therapy for disease progression between February 2018 to May 2023 were included. Patients were excluded if they received targeted therapy as subsequent systemic treatment. The primary endpoint was real-world progression-free survival (rwPFS) of post-durvalumab treatment. Key secondary outcomes included physician assessed response, overall survival (OS), and subgroup analyses to identify biomarkers which may predict benefit from IO retreatment. Results: A total of 66 patients met inclusion criteria, of which 39 (59%) received subsequent chemotherapy alone and 27 (41%) received IO-containing therapy. Of those who received IO-containing treatments, 18 received chemotherapy plus IO (chemoIO) and 9 received IO alone. Durvalumab was discontinued for therapy completion (chemotherapy: 18%, IO: 26%), disease progression (chemotherapy: 54%, IO: 48%), or side effects (chemotherapy: 26%, IO: 19%). No significant difference was observed between median rwPFS of chemotherapy versus IO-containing therapy (7.0 months vs 5.8 months, respectively; p = 0.9419) or OS (13.0 months vs 12.6 months, respectively; p = 0.5769). Notably, patients in our cohort who received IO alone had a numerically longer rwPFS compared to chemoIO (12.6 months vs 5.8 months, respectively; p = 0.3951), as well as a numerically longer OS (12.6 months vs 6.4 months, respectively; p = 0.8885). Conclusions: This study found that there were no statistically significant differences in median rwPFS or OS between chemotherapy or IO-based regimens following the conclusion of durvalumab consolidation. Interestingly, we observed a numerically improved rwPFS and OS in those who received IO alone compared to chemoIO, which suggests there may be key clinical or molecular features that may help identify patients who benefit from IO therapy. We acknowledge the limitations of this small, retrospective study. The efficacy of IO-based regimens post-durvalumab warrants further investigation in a larger, prospective manner to assess the risks and benefits of IO retreatment.