Background

Stage III NSCLC represents a heterogeneous group of patients (pts). The treatment of such pts may be a challenge, requiring a multimodal approach and the need to adapt the treatment to the disease and the patient. Definitive cure rates, as well as long-term prognosis differ significantly between the sub-stages.

Methods

This retrospective study has as primary endpoint the evaluation of the impact of concomitant chemoradiotherapy (ChR) and concomitant ChR at day 50 (chemoradiotherapy (Ch) starts D1 and radiotherapy starts concomitantly with Ch at D50) (ChR50) in the survival of stage III NSCLC pts. The secondary endpoint is to assess survival by age group. The data were collected and analyzed using the software “IBM SPSS”^® v25.

Results

From January 2017 to December 2020, 66pts were eligible as they underwent ChR (n = 30) or ChR50 (n = 36). In this sample: 72.7% (n = 48) were male; median age at diagnosis was 66 years (yrs); 53% (n = 35) had ECOG-PS of 0; 37.9% (n = 25) were active smokers; 51.4% (n = 34) of the tumors were adenocarcinoma (ADC); 50% (n = 33) were stage IIIB (AJCC 7th edition) and PDL1 expression was positive in 32 pts. In this study, 52pts had a disease progression, 25pts treated with ChR and 27pts treated with ChR50 (4-year follow-up). PFS was 13.92mos in the ChR group and 12.70mos in the ChR50 group (p value = 0.014); PFS was 10.8mos in the group <65yrs (n = 23) and 15.2mos in the group ≥ 65yrs (n = 29) (p value = 0.226); ADC showed higher PFS than SCC (17 vs 9.5mos) (p value = 0.059). The mortality rate in this study was 50% (n = 33), 20pts treated with ChR and 13pts treated with ChR50 (4-year follow-up). OS was not influenced by the administered scheme. OS was 13.6mos in the group <65yrs and 15.1mos in the group ≥ 65yrs (p value = 0.211). Histology, age, smoking habits, PDL1, ECOG-PS and stage did not show SS in their relationship with PFS and OS.

Conclusions

PFS was influenced by the treatment (ChR) instituted and this result was independent of age, smoking habits, PDL1, ECOG-PS and stage. PFS was higher in the group ≥ 65yrs, although it is a trend that cannot be assumed due to the small sample size. PFS was higher in the group ≥ 65yrs, although it is a trend that cannot be assumed due to the small sample size.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

EGFR TKI's are a mainstay in the treatment of metastatic NSCLC with EGFR mt+, however their use in the curative setting is not yet standard of care. Recently, combination of TKI and chemotherapy has been shown to improve ORR, PFS and OS in the metastatic setting. Induction therapy with chemotherapy with or without radiotherapy is an established approach in stages II and III, however no data exist for induction therapy with TKI and chemotherapy in EGFR mt+ NSCLC. Here we describe the outcome of 10 pts with EGFR mt+ NSCLC, all stage III, treated with 1^st and 3^rd generation TKI in combination with chemotherapy as induction therapy.

Methods

10/10 pts had adenocarcinoma, 6 with EGFR exon 19 and 4 with EGFR L858R. Pts received erlotinib (n = 2), gefitinib (n = 5) or osimertinib (n = 3) for 10 days followed by TKI in combination with chemotherapy (taxane /cisplatin (n = 5), paclitaxel/carboplatin (n = 5)) for 3 cycles. RECIST radiologic response as well as regression grading according to Junker et al. was performed on the resection specimens.

Results

7 pts are evaluable for response, 3 patients treated with osimertinib are still on therapy. 7/7 pts achieved radiologic PR after 2 cycles, all tumors were R0 resected. pCR was achieved in the primary tumor in 2/7 evaluable pts, 5/7 pts did not achieve pCR or MPR in the primary tumor. In the mediastinal lymph nodes, MPR was achieved in 6/7 evaluable pts (1 pCR). 2 patients achieving pCR in the primary tumor, 5 pts relapsed at 8 to 17 (median 12) months, 3/5 with CNS as 1st relapse site and 2/5 with other sites. With a median follow up of 46 months (13–68), 6 pts are alive at 2+, 2+, 2+, 13+, 44+, 67+ months and one patient died in CR of secondary cancer at 51 months. Median OS of the 10 pts was 51 months and mPFS was 17 months. Further data with respect to osimertinib + chemotherapy induction will be presented at the meeting.

Conclusions

In conclusion 1^st and 3^rd generation TKI-chemotherapy induction in EGFR mt+ NSCLC is feasible, leads to high MPR rates in mediastinal lymph nodes and lower pathologic response rates in the primary tumors. pCR in the primary tumor may predict better outcome. As CNS is the most frequent site of relapse this site might be of special interest in further induction studies on EGFR mt+ NSCLC, including NeoADAURA study.

Legal entity responsible for the study

University Hospital Internal Medicine-Oncology, Pius Hospital Oldenburg, University Oldenburg.

Funding

Has not received any funding.

Disclosure

F. Griesinger: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Siemens; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Lilly; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Takeda; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AbbVie. J. Roeper: Honoraria (self): Boehringer Ingelheim; Honoraria (self): AstraZeneca; Honoraria (self): Roche. M. Sebastian: Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Tesaro; Honoraria (self): Amgen; Honoraria (self): Pfizer; Honoraria (self): Lilly; Honoraria (self): Roche; Honoraria (self): Takeda; Honoraria (self): BionTech; Honoraria (self): Novartis; Honoraria (self): CuraVec. All other authors have declared no conflicts of interest.

Background

Multimodality therapy offers the best opportunity to improve the prognosis of pathologic N2 (pN2) NSCLC. Upfront surgery followed by adjuvant therapy is currently performed in resectable N2 NSCLC. Aim: To evaluate long-term clinical outcomes and prognostic factors of upfront surgery as first-line therapy in pN2.

Methods

Retrospective review of pN2 NSCLC (2007–2017). Exclusion criteria: other malignancies; incomplete surgical resections; incomplete data. The preoperative staging was performed according to well-established/widely accepted protocols. The multidisciplinary team determined treatment strategies for biopsy-proven N2. Upfront-surgery was considered if primary tumour was resectable, with single-station mediastinal nodal metastases, no evidence of extra-nodal invasion. OS/DFS were estimated using Kaplan–Meier. Cox hazards model was used for univariable/multivariable analyses.

Results

285 R0 resections were included; 159 (55.8%) patients received induction chemotherapy.

Univariable/multivariable Cox analyses showed that older age and comorbidities were significantly associated with worse OS. Mean follow-up time was 39.6 ± 24.7 months. At follow-up-end, 127 (44.6%) had died. For the induction chemotherapy group, the median OS was 49 months (95%CI: 38–70 months) and 5-year OS was 44.4%. Median and 5-year OS for upfront surgery group were 66 months (95%CI: 40–119) and 66.3%, respectively. There were no statistically significant differences between treatments(p = 0.48). 137 (48.1%) developed recurrence. 5-years DFS was 17% (95%CI: 11–25) for induction chemotherapy and 22% (95%CI: 9–32%) for upfront surgery; there were no statistically significant differences (p = 0.93). Based on cN, no significant differences were observed (OS, p = 0.36/DFS, p = 0.65).

Conclusions

Upfront surgery as first-line therapy in pN2 NSCLC showed favourable clinical outcomes. Therefore, it should be considered as a treatments option in resectable N2 NSCLC.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Retrospective studies have shown good clinical outcomes with 3D-conformal radiotherapy (RT) for locoregional recurrence of non-small cell lung cancer (NSCLC). We investigated the outcomes of patients given salvage thoracic treatment using intensity-modulated radiotherapy (IMRT) in our institution.

Methods

We retrospectively reviewed all patients treated with radical RT or chemoradiotherapy (CRT) at the Royal Free Hospital for locoregional recurrence of NSCLC between November 2016 and November 2019. All patients had FDG-PET staging prior to surgery and at time of recurrence.

Results

14 patients were identified with a median age of 68 years (range 55–78 years). The most common histological type was adenocarcinoma (71%). All patients had lobectomy, and the median time to recurrence from surgery was 16 months (range 3–48 months). All patients had nodal recurrence, with 50% having multiple station recurrence. 9 patients received concurrent CRT, 1 received sequential CRT and 4 received RT alone. Most patients had low-volume recurrence with a median GTV volume of 19 cm³ (range 4–89 cm³). All patients were treated with volumetric modulated arc IMRT. Patients receiving sequential CRT or RT alone received 55Gy in 20 fractions. Patients who received concurrent CRT were treated with 60–66 Gy in 30–33 fractions with cisplatin-vinorelbine. Only one patient experienced grade 3 toxicity requiring hospital admission for dehydration. Median follow-up was 16 months (range 6–44 months). 12-month overall survival was 86%. The sample was not large enough to detect any significant correlates with prognostic factors.

Conclusions

Excellent early survival outcomes and low toxicity were seen with salvage IMRT for nodal recurrence of NSCLC after lobectomy. A larger sample size would be needed to assess prognostic factors and compare the outcomes from CRT and RT alone.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

LCNEC are rare pulmonary tumours conferring a poor prognosis. Achieving a pathological diagnosis is challenging, often ultimately made on resected surgical specimens. We hypothesise that EBUS-TBNA can provide cytology in a minimally invasive procedure on which diagnosis can be achieved, allowing treatment planning.

Methods

A review of a prospectively maintained EBUS database between January 2014 and December 2019 in our institute was conducted to identify all those with a final cytological diagnosis of NSCLC with NE morphology. All procedures utilised Rapid On-Site Evaluation (ROSE) by a consultant cytopathologist. Diagnoses of small cell carcinoma and low-grade neuroendocrine tumours were excluded. Pathological diagnoses were made according to IASLC/ATS/ERS criteria.

Results

A total of 2456 patients underwent EBUS at our institute in the study period. 35 possible LCNEC patients were identified, age range 40–89 years (mean 69). Of these 31 had a final cytological diagnosis of NSCLC with NE morphology (NE markers positive), 3 of which had a small cell carcinoma component. Four of the 35 cases had negative NE markers but were clinically considered to be LCNEC. At ROSE, the cases were called carcinoma (n = 13), NSCLC (n = 14), small cell carcinoma (n = 5), NE carcinoma (n = 2) and no malignant cells (n = 1). Of 5 cases called small cell carcinoma at ROSE, 4 had positive NE markers. LCNEC EBUS samples were either from the primary lesion (n = 2) or from mediastinal/hilar lymph nodes (n = 33). Most LCNEC cases were advanced with 17/35 at stage III disease and 13/35 presenting at stage IV and the remainder (5/35) stage I and II. Three patients had further histological confirmation from other sites (ultrasound guided biopsy of primary lesion and two post-operative surgical specimens) corroborating the diagnosis.

Conclusions

All our cases with further histology sampling were confirmed LCNEC. As most of our patients presented with advanced disease, the majority had no histological confirmation, making definite conclusions on the specificity and sensitivity of cytology alone difficult. Overall, we have demonstrated that EBUS-TBNA is a suitable method to provide material to make an initial diagnosis of LCNEC.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Approximately 10% of patients with newly diagnosed non-small cell lung cancer (NSCLC) will have brain metastases. National Institute for Health Care Excellence (NICE) recommends that patients with curative intent stage II and III NSCLC should have pre-treatment CT or MRI head, respectively. Early detection and management of brain metastases may slow disease progression and increase survival.

Methods

Patients diagnosed with NSCLC between January 2019 and October 2020 were reviewed. The local imaging portal was used to review neuroimaging. Two PDSA cycles were completed following baseline audit. These included presenting results at Lung MDT and creating a prompt on the Lung MDT list to remind clinicians to request appropriate neuroimaging.

Results

44 patients diagnosed with curative intent stage II and III NSCLC between January 2019 to October 2020 were audited for pre-treatment neuroimaging. At baseline, correct neuroimaging was performed in 40% of patients with stage II and III disease. Incorrect imaging was performed in 0% stage II and 20% stage III disease. No neuroimaging was performed in 60% stage II and 40% stage III patients. Following 2 PDSA cycles, correct neuroimaging was obtained in 33.3% stage II and 72.7% stage III disease. Incorrect imaging was performed in 0% stage II and 9% stage III disease. No neuroimaging was performed in 66.7% stage II and 18.2% stage III patients.

Conclusions

Significant improvement has been demonstrated in neuroimaging for stage III disease. However, increasing compliance for stage II has been more challenging. We feel our experience should prompt all centres to audit this practice, as despite clinicians’ belief that these investigations were being done appropriately, the figures do not support this and interventions were necessary. We have since implemented a third intervention and a re-audit is planned in 6 months.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

In patients with resected, stage II-III NSCLC, the 5-year disease-free survival (DFS) rate with SoC adjuvant chemotherapy is ∼40%. Despite advances with immunotherapy (IO) in the metastatic setting, overall survival (OS) rates for patients with recurrence remain low. Detection of minimal residual disease (MRD), as indicated by circulating tumor DNA (ctDNA), may indicate the presence of clinically indiscernible residual tumor following curative-intent therapy and enable earlier therapeutic intervention, thereby improving outcomes in patients at highest risk of recurrence. In the phase III PACIFIC trial, consolidation durvalumab improved survival outcomes in patients with unresectable, stage III NSCLC without detectable disease progression after curative-intent chemoradiotherapy (Antonia, 2018), suggesting MRD is vulnerable to additional therapy, particularly IO, a concept supported by recent data in MRD+ patients (Moding, 2020). MERMAID-2 will assess the efficacy and safety of durvalumab, versus placebo, in patients with resected, stage II-III NSCLC who become MRD+ after curative-intent therapy.

Trial design

MERMAID-2 (NCT04642469) is a global, phase III, double-blind multicenter study that is currently recruiting patients. Patients with histologically confirmed EGFR/ALK wild-type stage II-III NSCLC who have completed curative-intent therapy (complete resection + optional neoadjuvant and/or adjuvant therapy) will be enrolled in a 96-week surveillance period. During this period, patients will be monitored regularly for MRD emergence via ctDNA analysis of plasma samples, based on personalized MRD panels. Patients who become MRD+ during the surveillance period will be further evaluated to confirm eligibility (no disease recurrence visible on imaging; known PD-L1 status) and ∼284 MRD+ patients will be randomized 1:1 to receive durvalumab 1500 mg IV or placebo q4w, up to 24 months or until investigator-assessed disease recurrence. The primary endpoint is DFS in patients with PD–L1 tumor cell expression ≥1%. Secondary endpoints include DFS in the full analysis set, progression-free survival, OS, time to subsequent therapy, patient-reported outcomes, and safety.

Clinical trial identification

NCT04642469.

Editorial acknowledgement

Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Andrew Gannon and Connor Keating of Cirrus Communications (New York, NY), an Ashfield company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

D.R. Spigel: Research grant/Funding (institution), Conduct of clinical trials and consultancy: AstraZeneca/BMS/Celgene/EMD Serono/Roche/Genetech/GSK/Ipsen/ Novartis/Takeda; Research grant/Funding (institution), Conduct of clinical trials: Aeglea Biotherapeutics/Agios/Astellas Pharma/BIND Therapeutics/Celldex Therapeutics/Clovis/ Daiichi Sankyo/Eisai/Eli Lilly/G1 Therapeutics/GRAIL; Research grant/Funding (institution), Conduct of clinical trials: ImClone Systems/Janssen/MedImmune/Merck/ Nektar Therapeutics/Neon Therapeutics/Tesaro/ Transgene/UT Southwestern/Cyteir Therapeutics/Apollomics/Elevation Oncology; Research grant/Funding (institution), Payment to institution for consulting services: Aptitude Health/Bayer/Dracen Pharmaceuticals/Exelixis/Iksuda Therapeutics/ Intellisphere/ Jazz Pharmaceuticals/ Mirati Therapeutics/ Molecular Templates /Puma Biotechnology. S. Peters: Advisory/Consultancy, Personal fees (advisory board and honorarium): AbbVie/Amgen/AstraZeneca/Bayer/Biocartis/Boehringer Ingelheim/Bristol-Myers Squibb/Clovis/Daiichi Sankyo/ Debiopharm/Eli Lilly/F, Hoffman-La Roche/Foundation Medicine/Illumina/Janssen/MSD/Merck Serono/Merrimack/Novartis; Advisory/Consultancy, Personal fees (advisory board and honorarium): Pharma Mar/ Pfizer/Regeneron/Bioinvent/Sanofi/Seattle Genetics and Takeda; Speaker Bureau/Expert testimony, Personal fees (talks and honorarium): AstraZeneca/Boehringer Ingelheim/ Bristol-Myers Squibb/Eli Lilly/F. Hoffmann la Roche/MSD/Novartis/Pfizer/Takeda/Sanofi; Research grant/Funding (self), Non-financial support for clinical trial investigation: Amgen/AstraZeneca/Boehringer Ingelheim/ Bristol-Myers Squibb/Clovis/F. Hoffmann-La Roche/Illumina/MSD/Merck Serono/Novartis /Pfizer. M. Tsuboi: Advisory/Consultancy, Personal fees for advisory boards and lectures: AstraZeneca KK/Chugai Pharmaceutical/MSD; Advisory/Consultancy, Personal fees for advisory boards: Novartis; Research grant/Funding (self), Personal fees for lectures: Medtronic Japan/ONO Pharmaceutical/Johnson & Johnson Japan/Eli Lilly Japan/Bristol-Myers Squibb KK/Teijin Pharma/Taiho Pharma; Research grant/Funding (institution), Research funding: Boehringer Ingelheim Japan; Research grant/Funding (institution), Commissioned research for clinical trials: MSD/AstraZeneca KK/ONO Pharmaceutical/ Bristol-Myers Squibb KK/Eli Lilly Japan. J. Chaft: Advisory/Consultancy: AstraZeneca/Bristol-Myers Squibb/Genentech/Flame Biosciences/Merck. D. Harpole: Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy: AstraZeneca/Medtronic. F. Barlesi: Research grant/Funding (self), Personal fees: AstraZeneca/Bayer/Bristol-Myers Squibb/Boehringer Ingelheim/Eli Lilly Oncology; Research grant/Funding (self), Personal fees: F. Hoffmann–La Roche Ltd/Novartis/Merc/MSD/Pierre Fabre/Pfizer/Takeda. C. Abbosh: Advisory/Consultancy: AstraZeneca; Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Research grant/Funding (self), Contracted/support research grant: AstraZeneca; Research grant/Funding (institution), Current AstraZeneca Physician Fellow (grant to University College London): AstraZeneca; Licensing/Royalties, Royalty/intellectual property/patent holder - author on two pending patents: AstraZeneca. H. Mann: Full/Part-time employment: AstraZeneca. R. May: Full/Part-time employment: AstraZeneca. P.A. Dennis: Full/Part-time employment: AstraZeneca; Shareholder/Stockholder/Stock options: AstraZeneca. C. Swanton: Honoraria (self), Research grant/Funding (self), Chief Investigator for the MeRmaiD1 clinical trial: AstraZeneca; Advisory/Consultancy, Chief Investigator for the MeRmaiD1 clinical trial: AstraZeneca; Honoraria (self), Research grant/Funding (self): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (self): Pfizer; Honoraria (self), Research grant/Funding (self): Roche-Ventana; Honoraria (self), Research grant/Funding (self): Ono Pharmaceutical; Research grant/Funding (self), collaboration in minimal residual disease sequencing technologies: Archer Dx Inc; Research grant/Funding (self): Boehringer Ingelheim; Honoraria (self): Novartis; Honoraria (self): GSK; Honoraria (self): Celgene; Honoraria (self): MSD; Honoraria (self): Illumina; Honoraria (self): Genentech; Honoraria (self): Sarah Cannon Research Institute; Honoraria (self): Medixci; Honoraria (self): Bicycle Therapeutics; Shareholder/Stockholder/Stock options: GRAIL; Shareholder/Stockholder/Stock options: Apogen Biotechnologies; Shareholder/Stockholder/Stock options: Epic Biosciences; Honoraria (self), Shareholder/Stockholder/Stock options: Achilles Therapeutics; Intellectual property [patents issued]: Assay technology to detect tumour recurrence (PCT/GB2017/053289), Targeting neoantigens (PCT/EP2016/059401), Identifying patient response to immune checkpoint blockade (PCT/EP2016/071471), Determining HLA LOH (PCT/GB2018/052004), Predicting survival rates of patients with cancer (PCT/GB2020/050221), Identifying patients who respond to cancer treatment (PCT/GB2018/051912), Detecting tumour mutations (PCT/US2017/28013), Insertion/deletion mutation targets (PCT/GB2018/051892); Other: Charles Swanton is Royal Society Napier Research Professor (RP150154). His work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169) and the Wellcome Trust (FC001169). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Charles Swanton is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Centre of Excellence, the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Research Professorship Enhancement Award (RP/EA/180007), the NIHR BRC at University College London Hospitals, the CRUK-UCL Centre, Experimental Cancer Medicine Centre and the Breast Cancer Research Foundation, USA (BCRF). His research is supported by a Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (SU2C-AACR-DT23–17). Stand Up To Cancer is a programme of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. Charles Swanton also receives funding from the European Research Council (ERC) under the European Union's Seventh Framework Programme (FP7/2007–2013) Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union's Horizon 2020 research and innovation programme (835297) and Chromavision from the European Union's Horizon 2020 research and innovation programme (665233). All other authors have declared no conflicts of interest.

Background

Adjuvant and neoadjuvant therapies have been proposed to improve the prognosis of patients (pts) with stage II/IIIA lung cancer but have provided only modest survival benefits. When added to chemotherapy, PD-(L)1 inhibitors have resulted in enhanced antitumor activity versus chemotherapy alone, but their ability to limit relapse in pts who have undergone surgical resection has not yet been fully elucidated. Tislelizumab, a monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis. Tislelizumab, as a single agent and in combination with chemotherapy, has demonstrated a manageable tolerability profile and efficacy in pts with advanced NSCLC.

Trial design

This phase III, randomized, double-blind study (NCT04379635) compares the efficacy of neoadjuvant tislelizumab or placebo + platinum-based doublet chemotherapy followed by adjuvant tislelizumab or placebo. Adult pts (n≈380) with histologically confirmed, squamous (sq) or nonsquamous (nsq) stage II/IIIA resectable NSCLC are eligible; key exclusion criteria include prior systemic anticancer treatment for lung cancer or known EGFR mutations or ALK rearrangements. In the neoadjuvant phase, pts will be randomized 1:1 to receive tislelizumab (Arm A) or placebo (Arm B) plus cisplatin/carboplatin + paclitaxel or pemetrexed on Day 1 of each 3-wk cycle for 3–4 cycles. Patients will be stratified by histology (sq vs nsq), disease stage (II vs IIIA), and PD-L1 expression (≥1% vs <1%). After surgery, adjuvant therapy (tislelizumab [A]; placebo [B]) will be administered on Day 1 of each 6-wk cycle for up to eight cycles. Major pathological response rate (proportion of pts with ≤10% residual viable tumors) and event-free survival per RECIST v1.1 are dual primary endpoints. Secondary endpoints include overall survival, objective response rate, disease-free survival, pathological complete response rate, safety/tolerability (assessed by monitoring incidence and severity of adverse events), and health-related quality-of-life measures.

Clinical trial identification

NCT04379635.

Editorial acknowledgement

Writing and editorial assistance was provided by Stephan Lindsey, PhD, and Elizabeth Hermans, PhD (OPEN Health Medical Communications, Chicago, IL), and funded by the study sponsor.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

R. Wang: Full/Part-time employment: BeiGene, Ltd. Y. Ma: Full/Part-time employment: BeiGene, Ltd. X. Liang: Full/Part-time employment: BeiGene, Ltd. All other authors have declared no conflicts of interest.

Background

About 30% of pts with NSCLC present with Stage III disease; most pts are deemed inoperable. In the phase III PACIFIC trial, durvalumab, a selective, high–affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, significantly improved progression-free and overall survival (PFS/OS) in pts with unresectable, Stage III NSCLC without disease progression (PD) after ≥2 cycles of platinum-based concurrent chemoradiotherapy (cCRT). Consequently, the ‘PACIFIC regimen’ is now standard of care in this setting for pts with good performance status (PS). Pts with poor PS, comorbidities, or advanced age (a large proportion of this population) may be ineligible for chemotherapy (CT) due to expected high toxicity. These pts typically receive definitive radiotherapy (RT) alone, with poor survival rates (3-year: 5–10%). Based on the PACIFIC trial data and the strong biological rationale for combining RT with anti-PD-L1 consolidation therapy, durvalumab following RT could provide additional survival benefit vs RT alone in these pts. The DUART study will assess safety and tolerability of durvalumab following RT in pts with unresectable, Stage III NSCLC ineligible for CT.

Trial design

DUART (NCT04249362) is a phase II, open-label, single-arm, multicenter, international study enrolling pts aged ≥18 years with histologically/cytologically confirmed unresectable, Stage III NSCLC, deemed ineligible for CT by investigator/physician criteria, with no PD following RT (40–66 Gy; completed ≤42 days prior to receiving durvalumab), who have not received prior immunotherapy, and with ECOG PS ≤2. About 150 pts will be enrolled into 2 cohorts (1:1) according to prior RT dose delivered in enrolling centres (A: standard RT, 60 Gy ± 10% or hypofractionated bioequivalent dose [BED]; B: palliative RT, 40 to <54 Gy or hypofractionated BED). Pts will receive 1500 mg durvalumab iv every 4 weeks for up to 12 months or until PD or unacceptable toxicity. The primary endpoint is safety and tolerability, defined by incidence of grade 3/4 adverse events possibly related to treatment within 6 months of first dose. Secondary efficacy endpoints include PFS, OS, objective response rate and duration of response.

Clinical trial identification

NCT04249362.

Editorial acknowledgement

Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Connor Keating of Cirrus Communications (Macclesfield, UK), an Ashfield company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca plc.

Funding

AstraZeneca.

Disclosure

A.R. Filippi: Non-remunerated activity/ies, Non-financial support: AstraZeneca; Advisory/Consultancy, Advisory board: AstraZeneca/Roche; Speaker Bureau/Expert testimony, Speaker's bureau: MSD/Ipsen. R. Dziadziuszko: Non-remunerated activity/ies, Non-financial support: AstraZeneca/Roche; Research grant/Funding (self), Personal fees: AstraZeneca/Roche; Research grant/Funding (self), Personal fees: Foundation Medicine/Seattle Genetics/Takeda/Boehringer Ingelheim/Novartis/MSD/Pfizer/Regeneron. M.R. Garcia Campelo: Research grant/Funding (self), Personal fees: AstraZeneca/Roche/Lilly/Novartis/MSD/Takeda/Pfizer. J-B. Paoli: Research grant/Funding (self), Personal fees relating to clinical trials in lung/renal/bladder/prostate cancer: MSD/Bristol-Myers Squibb/Pfizer/Janssen. W. Sawyer: Full/Part-time employment, Contractor: AstraZeneca. I.E. Díaz Pérez: Full/Part-time employment: AstraZeneca; Shareholder/Stockholder/Stock options: AstraZeneca.

Background

IMpower132 is a phase III study evaluating atezo + pem + cis/carbo (APP) in stage IV non-squamous (nsq) EGFR/ALK-negative NSCLC. The coprimary PFS endpoint was met in the ITT population at the primary analysis (HR 0.60; 95% CI 0.49, 0.72; P < 0.0001) (Papadimitrakopoulou, WCLC 2018). The coprimary OS endpoint was not met at the final analysis, although numerical improvement in mOS was seen in the APP vs control arm (Nishio, ESMO Asia 2020). Here we report primary data from the IMpower132 China cohort, including 1 patient (pt) from the global population and 162 pts from the China extension phase.

Methods

In the China cohort, treatment-naive pts with nsq stage IV EGFR/ALK-negative NSCLC were randomised 1:1 to receive 4 or 6 cycles of cis 75 mg/m² + pem 500 mg/m² Q3W alone (PP arm) or with atezo 1200 mg Q3W (APP arm) followed by maintenance pem (PP arm) or atezo + pem (APP arm). Coprimary endpoints were investigator-assessed PFS (RECIST 1.1) and OS; key secondary endpoints included ORR, DOR and safety.

Results

A total of 82 (APP) and 81 (PP) pts were enrolled. At data cutoff (18 July 2019), median survival follow-up was 11.7 mo in all 163 pts. Baseline characteristics were generally balanced between arms. At the final PFS analysis, mPFS was 8.3 (APP) vs 5.8 mo (PP; HR 0.73; 95% CI 0.5, 1.08). At the interim OS analysis conducted at the time of the final PFS analysis, mOS was not estimable in both arms (HR 0.70; 95% CI 0.40, 1.24). In the APP and PP arms, 31% and 40% of pts received subsequent non-protocol anticancer therapies, including immunotherapy in 0 (APP) and 12% (PP). Confirmed ORR was 56% (APP) and 27% (PP); mDOR was 6.7 (APP) and 8.5 (PP) mo. Gr 3/4 TRAEs occurred in 62% (APP) and 46% (PP) of pts; 2% of pts in each arm had Gr 5 TRAEs. AEs of special interest occurred in 74% (APP) and 42% (PP) of pts; these were Gr 3/4 in 10% (APP) and 6% (PP).

Conclusions

In the IMpower132 China cohort, PFS benefit was seen in the APP vs PP arm, consistent with the global population. Interim OS data, though immature, showed numerical OS benefit in the APP vs PP arm. The safety profile of APP was consistent with the known risks of the individual treatment components; no new safety signals were identified.

Clinical trial identification

NCT02657434.

Editorial acknowledgement

Medical writing assistance for this abstract was provided by Derrick Afful, PhD, and Kia Walcott, PhD, of Health Interactions.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffmann-La Roche, Ltd.

Disclosure

S. Lu: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Hutchison; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Heng Rui Beigene; Research grant/Funding (institution): Roche; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Hansoh; Speaker Bureau/Expert testimony: Hengrui Therapeutics; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Hutchison MediPharma; Advisory/Consultancy: Simcere; Advisory/Consultancy: ZaiLab; Advisory/Consultancy: GenomiCare; Advisory/Consultancy: Yuhan Corporation; Advisory/Consultancy: PrIME Oncology; Advisory/Consultancy: Menarini; Advisory/Consultancy: Roche. J. Xia: Full/Part-time employment: Roche (China) Holding Ltd. J. Yi: Full/Part-time employment: Genentech; Shareholder/Stockholder/Stock options: Roche; Spouse/Financial dependant: Genentech. All other authors have declared no conflicts of interest.

Background

Avelumab (anti–PD-L1 mAb) is approved in Merkel cell carcinoma, urothelial carcinoma and in combination with axitinib for renal cell carcinoma in various countries. Preclinical data suggest avelumab may have an enhanced treatment effect in combination with cetuximab (anti–EGFR mAb) and cisplatin, including in NSCLC. We report results of avelumab plus cetuximab and platinum-based chemotherapy in patients with advanced squamous NSCLC.

Methods

This phase IIa study (NCT03717155) enrolled patients with previously untreated histologically confirmed, stage IV, recurrent or metastatic, squamous NSCLC without EGFR/ALK mutations. Patients received avelumab 800 mg (days 1 and 8); cetuximab 250 mg/m² (day 1) and 500 mg/m² (day 8); cisplatin 75 mg/m² (day 1); and gemcitabine 1250 mg/m² (days 1, 8) for 4 × 3-week cycles followed by avelumab 800 mg and cetuximab 500 mg/m² maintenance every 2 weeks until progression, unacceptable toxicity, or withdrawal. The primary endpoint was investigator-assessed confirmed best overall response (BOR) per RECIST 1.1.

Results

43 patients were enrolled. As of July 2, 2020 (primary analysis), 15 patients (34.9%) remained on study treatment. Confirmed BOR was partial response (PR) in 13 patients (ORR, 30.2% [95% CI, 17.2%–46.1%]; disease control rate, 79.1%). Median duration of confirmed response was 7.1 months and 60.8% of responses lasted ≥6 months. Overall, 23 patients had unconfirmed or confirmed PR (ORR, 53.5% [95% CI, 37.7%–68.8%]). Treatment-related adverse events (TRAEs) occurred in 38 patients (88.4%), which were grade ≥3 in 24 (55.8%; most common was neutropenia [n = 12; 27.9%]). No treatment-related deaths occurred. As of Nov 4, 2020 (updated analysis), median progression-free and overall survival were 6.1 and 10.0 months, respectively. Updated data, including biomarker data will be presented.

Conclusions

The combination of avelumab, cetuximab, cisplatin and gemcitabine showed clinical activity and a manageable safety profile with no additional safety signals for avelumab or cetuximab.

Clinical trial identification: NCT03717155.

Editorial acknowledgement

Medical writing support was provided by Abhijith Thippeswamy and Mark Holland of ClinicalThinking and was funded by Merck KGaA, Darmstadt, Germany and Pfizer.

Legal entity responsible for the study

Merck KGaA, Darmstadt, Germany and Pfizer.

Funding

This study was sponsored by Merck KGaA, Darmstadt, Germany and is part of an alliance between Merck KGaA and Pfizer.

Disclosure

B. Szima: Research grant/Funding (self), Principle Investigator: IQVIA. E. Felip Font: Advisory/Consultancy: AbbVie; Advisory/Consultancy: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Blue Print Medicines; Advisory/Consultancy, Speaker Bureau/Expert testimony: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: Janssen; Advisory/Consultancy: Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy: Puma Biotechnology; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Sanofi Genzyme; Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Speaker Bureau/Expert testimony: Medscape; Speaker Bureau/Expert testimony: PeerVoice; Speaker Bureau/Expert testimony: Springer; Speaker Bureau/Expert testimony: Touch Independent Medical Education; Speaker Bureau/Expert testimony: CME Outfitters; Speaker Bureau/Expert testimony: Prime Oncology; Research grant/Funding (institution), Grant for Oncology Innovation: Fundacion Merck Salud; Officer/Board of Directors, Independent member of the board: Grifols. D. Vicente Baz: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merch Sharp & Dohme. S. Ponce Aix: Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: AstraZeneca. O. Juan-Vidal: Advisory/Consultancy, Speaker Bureau/Expert testimony: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche/Genentech; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Takeda; Advisory/Consultancy: Eli Lilly. Z. Szalai: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: GlaxoSmithKline. A. Calles Blanco: Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: Takeda; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer Ingelheim. R. Bernabe: Research grant/Funding (institution): Roche. K. Duecker: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck KgaA, Darmstadt, Germany. D. Zhou: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck KGaA, Darmstadt, Germany. A. Schroeder: Honoraria (self), Leadership role, Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck KGaA, Darmstadt, Germany; Shareholder/Stockholder/Stock options: GlaxoSmithKline; Shareholder/Stockholder/Stock options: Pfizer; Shareholder/Stockholder/Stock options: BioNTech; Shareholder/Stockholder/Stock options: Eisai. G. Guezel: Full/Part-time employment: Merck KGaA, Darmstadt, Germany. F. Ciardiello: Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Servier; Advisory/Consultancy: Symphogen; Research grant/Funding (institution): Pfizer. All other authors have declared no conflicts of interest.