Thorac Oncol Research Articles

CONFIRMing single-drug immune checkpoint blockade efficacy in mesothelioma

Mesothelioma is an uncommon cancer, but, despite a reduction in asbestos use in high-income countries in the past few decades, we are still facing a global epidemic of this disease. Immune checkpoint blockade had an inauspicious start in mesothelioma, when the anti-CTLA-4 antibody, tremelimumab, was shown to not improve overall survival compared with placebo in the second-line setting. 1 Maio M Scherpereel A Calabro L et al. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol. 2017; 18: 1261-1273 Summary Full Text Full Text PDF PubMed Scopus (271) Google Scholar However, outcomes from several subsequent single-arm clinical trials suggested anti-tumour activity of PD-1 or PD-L1 blockade in patients with mesothelioma. 2 Alley EW Lopez J Santoro A et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2017; 18: 623-630 Summary Full Text Full Text PDF PubMed Scopus (335) Google Scholar , 3 Quispel-Janssen J van der Noort V de Vries JF et al. Programmed death 1 blockade with nivolumab in patients with recurrent malignant pleural mesothelioma. J Thorac Oncol. 2018; 13: 1569-1576 Summary Full Text Full Text PDF PubMed Scopus (150) Google Scholar , 4 Okada M Kijima T Aoe K et al. Clinical efficacy and safety of nivolumab: results of a multicenter, open-label, single-arm, Japanese phase II study in malignant pleural mesothelioma (MERIT). Clin Cancer Res. 2019; 25: 5485-5492 Crossref PubMed Scopus (138) Google Scholar Objective tumour response rates ranged from 20–30%. Together with promising progression-free survival and overall survival outcomes, these trials triggered inclusion of single drug PD-1 inhibition as an option for subsequent-line therapy in some—but not all—clinical practice guidelines from as early as 2017. Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trialNivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy. Full-Text PDF Open Access

15 First-line platinum-based chemotherapy combined with PD-1/PD-L1 inhibitors (ICI) prevents hyperprogression in non-small cell lung cancer (NSCLC) patients by reducing circulating immature neutrophils

BackgroundHyperprogression (HPD) has been described in ≃14–26% of NSCLC patients upon single-agent ICI1 and has not been reported upon ICI and platinum-based chemotherapy (PCT) combinations. Both high circulating neutrophils2 and senescent T-cells3 correlated with HPD, however the exact neutrophils-T-cells interplay and the role of specific neutrophils subsets in driving HPD is unknown.MethodsNSCLC patients treated with 1st line ICI as single-agent or in combination with PCT were assessed for HPD and circulating neutrophils’ phenotype. HPD required 3 assessment (2 before ICI, 1 upon ICI) and was defined as delta tumor growth rate (TGR) (TGR upon ICI – TGR before ICI) >50% and/or TGR ratio (TGR upon ICI/TGR before ICI) ≥2. Circulating low density neutrophils (LDNs) subtypes were assessed by flow cytometry on peripheral blood mononuclear cells (PMBCs). LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs. Immature subtypes were defined as CD10- LDNs. T-cells were isolated from healthy donors and cocultured with patients‘ LDNs to characterize the neutrophils-T-cells interplay. LDNs subtypes were isolated from patients and treated in-vitro with cisplatin to assess cell death.Results46 NSCLC patients were treated with single-agent ICI and 17 with PCT+ICI (table 1). In the ICI single-agent cohort, PD and HPD occurred in 21 (41%) and 4 (9%) patients. Before ICI start, HPD patients had significantly higher median% of circulating immature CD10- LDNs neutrophils [43.5 (min 29.5; max 82.6) vs 10.3 (min 0.1; max 79.4), p=0.01] compared to PD patients (figure 1). In the ICI-PCT cohort no HPD was reported. 5 patients had baseline CD10- LDNs ≥ 43.5% (median% of CD10- LDNs in HPD patients upon single-agent ICI), 2 of them had stable disease and 3 PD upon ICI-PCT. In these 5 patients, CD10- LDNs significantly decreased during ICI-PCT compared to what observed in HPD patients upon single-agent ICI [median variation -43.4 (min -67.6, max -31.6) vs +6.9 (min -33, max +44), p= 0.03] (figure 2). After 7 days of coculture with T-cells, immature CD10- LDNs significantly reduced T-cells survival and promoted a T-cell senescent phenotype (CD28 loss, CD57 gain) impairing T-cells proliferation and increasing IFN-gamma production (figure 3). Cisplatin treatment significantly increased necrotic cell death among CD10- LDNs compared to CD10+ LDNs (figure 4).Abstract 15 Table 1Patients characteristics in the single-agent ICI and PCT+ICI cohortsAbstract 15 Figure 1Patterns of response, progression and hyperprogression to single-agent ICI and correlation with mature (CD10+) or immature (CD10-) LDNs’ subtypesAbstract 15 Figure 2Neutrophils dynamic variation upon treatment (5 patients with high baseline CD10- LDNs and PD/SD to chemo-ICI vs 4 patients with HPD upon single-agent ICI)Abstract 15 Figure 3Mature (CD10+) and immature (CD10-) LDNs in coculture with T-cells from an healthy donor differently influence CD8 and CD4 T-cells survival, proliferation, IFN-gamma production and expression of a senescent (CD28- CD57+) phenotype.Abstract 15 Figure 4Cisplatin in-vitro treatment at different concentration (1 uM and 5 uM) increases necrotic (7AAD expression) cell death preferentially of immature (CD10-) rather than mature (CD10+) LDNsConclusionsHigher baseline immature CD10- LDNs impair T-cell survival and promote T-cell senescence being a circulating biomarker of HPD upon single-agent ICI. The addition of PCT prevents HPD by inducing immature neutrophils cell death.ReferencesFerrara R, Mezquita L, Texier M, Lahmar J, Audigier-Valette C, Tessonnier L, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with pd-1/pd-l1 inhibitors or with single-agent chemotherapy. JAMA Oncol 2018;4:1543–52. https://doi.org/10.1001/jamaoncol.2018.3676Kim Y, Kim CH, Lee HY, Lee S-H, Kim HS, Lee S, et al. Comprehensive clinical and genetic characterization of hyperprogression based on volumetry in advanced non-small cell lung cancer treated with immune checkpoint inhibitor. J Thorac Oncol 2019;14:1608–18. https://doi.org/10.1016/j.jtho.2019.05.033Ferrara R, Naigeon M, Auclin E, Duchemann B, Cassard L, Jouniaux JM, et al. Circulating T-cell immunosenescence in advanced non-small cell lung cancer patients treated with single agent PD-1/PD-L1 inhibitors or platinum-based chemotherapy. Clin Cancer Res 2020. https://doi.org/10.1158/1078-0432.CCR-20-1420.Ethics ApprovalPatients blood was obtained after signature of informed consent and within an observational prospective study (INT 22_15) approved by local Institutional Ethical Committee.

SKYSCRAPER-03: A Phase III, Open-Label, Randomized Study of Atezolizumab Plus Tiragolumab Compared With Durvalumab in Patients With Locally Advanced, Unresectable, Stage III NSCLC Who Have Not Progressed After Platinum-Based Concurrent Chemoradiation

<h3>Purpose/Objective(s)</h3> Until recently, the standard of care for patients (pts) with locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) has been platinum-based concurrent chemoradiation (cCRT); however, the 5-year OS rates are poor (13–36%; Goldstraw et al. J Thorac Oncol 2015). Durvalumab (anti-PD-L1) monotherapy was recently approved for pts without progressive disease (PD) after cCRT. However, long-term OS data are not yet available and further evaluation of novel cancer immunotherapy combinations should be explored. Targeted inhibition of a novel checkpoint TIGIT/PVR, by the anti-TIGIT antibody tiragolumab, may amplify the anti-cancer activity of anti-PD-L1/PD-1 antibodies. In the phase II CITYSCAPE study (NCT03563716), tiragolumab plus atezolizumab (anti-PD-L1) was well tolerated and improved ORR compared with atezolizumab alone (31.3 vs 16.2%) in 1L pts with PD-L1+ (TPS ≥1%) metastatic NSCLC; with greater benefit in the PD-L1-high (TPS ≥50%) subset. We hypothesize that tiragolumab plus atezolizumab may provide greater clinical benefit vs single-agent anti-PD-L1 as maintenance therapy in pts with unresectable, stage III NSCLC who have not progressed after platinum-based cCRT. SKYSCRAPER-03 (NCT04513925) will determine if tiragolumab plus atezolizumab provides superior clinical benefit to durvalumab in this setting. Current data suggests that cCRT upregulates PD-L1 expression, potentially enabling PD-L1 low or negative tumors to derive benefit, so outcomes will be evaluated in all-comer (ITT) and PD-L1+ sub-populations. <h3>Materials/Methods</h3> Eligible pts (≥18 years) must have unresectable, stage III NSCLC without PD after ≥2 cycles of platinum-based cCRT per NCCN/ESMO guidelines, and without an EGFR mutation or ALK rearrangement; known PD-L1 status; ECOG PS 0–1. Approximately 800 pts will be randomized 1:1 to receive tiragolumab 840mg IV plus atezolizumab 1680mg IV Q4W or durvalumab 10mg/kg IV Q2W / 1500mg IV Q4W. Treatment will continue for up to 13 cycles of 28 days, or until unacceptable toxicity or symptomatic deterioration due to PD; in pts with radiographic PD (per RECIST v1.1) treatment may continue if evidence of ongoing clinical benefit. Stratification factors include PD-L1 status, histology (squamous vs non-squamous), staging (IIIA vs IIIB or IIIC) and ECOG PS (0 vs 1). Primary endpoint is independent review facility-assessed PFS in the ITT and PD-L1+ (TC ≥1%) populations. Secondary endpoints include investigator-assessed PFS, OS, ORR and DoR. Safety and biomarker analyses will be performed. Recruitment is ongoing. <h3>Results</h3> forthcoming <h3>Conclusion</h3> forthcoming

ES11.02 Advances in Thoracic Radiation in SCLC

ES11.02 Advances in Thoracic Radiation in SCLC

WS05.03 Treatment of Advanced and Metastatic NSCLC without Oncogenic Drivers: Balancing Cost and Efficacy

WS05.03 Treatment of Advanced and Metastatic NSCLC without Oncogenic Drivers: Balancing Cost and Efficacy

1224P Systematic review and meta-analysis of immunotherapy effectiveness for pretreated patients with non-small cell lung cancer harboring EGFR exon 20 insertions

EGFR exon 20 insertion (ex20ins) mutations are rare, and data on clinical outcomes with immunotherapy (IO) in these patients are scarce. Per National Comprehensive Cancer Network guidelines, IO monotherapy is not recommended over targeted therapies for non–small cell lung cancer (NSCLC) patients with an oncogenic driver. To determine the efficacy of IO monotherapy in the second-line setting and beyond (≥2nd-line) for EGFRex20ins+ NSCLC, we conducted a systematic review and meta-analysis of real-world objective response rate (ORR) data. We analyzed ORRs of ≥2nd-line IO monotherapies in EGFRex20ins+ NSCLC from: (1) PubMed literature search for clinical studies reporting ORR, disease control rate (DCR), or progression-free survival (PFS); (2) longitudinal data from the United States Flatiron Health Research Database; (3) a retrospective chart review from 12 German oncology centers; and (4) prior anticancer therapy and associated response data from a single-arm, phase I/II study of mobocertinib, an oral EGFR tyrosine kinase inhibitor targeting EGFRex20ins, in EGFRex20ins+ NSCLC patients previously treated with ≥2nd-line IO. From the meta-analysis of all data, the calculated ORR [95% confidence intervals] for ≥2nd-line IO monotherapy in patients with EGFRex20ins+ NSCLC was 3.5% [0.6%, 9.9%] (Table). Across sources (N=91), reported ORRs ranged from 0% to 14.3% (1/7 patients in single study), with 2 total responses; DCRs ranged from 23.8% to 30.0%, and median PFS ranged from 2.3 months to 4.0 months. Reported data were limited by small number of patients and studies reporting mixed lines of therapy (≥2nd-line).Table: 1224PData sourceReported ORR, n/N (%)Takeda M. (Oncotarget. 2018)1/7 (14.3%)LC-SCRUM-JAPAN/Udagawa (J Thorac Oncol. 2019)0/21 (0%)Yang G. (Lung Cancer. 2020)0/2 (0%)Flatiron database1/20 (5%)German chart review0/10 (0%)Mobocertinib study0/31 (0%)Meta-analysisMean ORR [2.5%, 97.5%]3.5% [0.6%, 9.9%] Open table in a new tab Results of this meta-analysis suggest that IO monotherapies are not effective in the ≥2nd-line setting for patients with EGFRex20ins+ NSCLC, which further highlights the need for novel treatment options in this population.

Thymectomy with angioplasty through a thoracoscopic subxiphoid approach with double elevation of the sternum in Masaoka stage III thymoma.

Thymectomy with angioplasty through a thoracoscopic subxiphoid approach with double elevation of the sternum in Masaoka stage III thymoma.

Abstract 503: Analytical comparison of a PD-L1 22C3 antibody LDT protocol on the BenchMark XT and PD-L1 IHC 22C3 pharmDx: Analysis of pan-tumor and esophageal cancer samples

Abstract Background: PD-L1 IHC 22C3 pharmDx is an FDA-approved companion diagnostic to pembrolizumab across multiple tumor types designed for use on the Autostainer Link 48 (AL48). Many pathology laboratories do not have access to the AL48 and therefore do not use PD-L1 IHC 22C3 pharmDx to assess PD-L1 status. As a result, these laboratories often assess PD-L1 using laboratory-developed tests (LDTs) on the Ventana BenchMark platform. We compared our PD-L1 22C3 antibody-based LDT on the BenchMark XT platform with PD-L1 IHC 22C3 pharmDx. Data using head and neck squamous cell carcinoma (HNSCC) and urothelial carcinoma (UC) samples alone have previously been presented (Vainer GW et al. 31st European Congress of Pathology; September 7-11, 2019). In the current study, we performed a pan-tumor analysis that also included samples from patients with esophageal SCC (ESCC). Methods: The LDT used for this analysis has been described (Neuman T et al. J Thorac Oncol. 2016;11:1863-1868). Tumor specimens from patients with HNSCC, UC, and ESCC were stained with the 22C3 antibody, scored using the LDT on the BenchMark XT platform, and compared with PD-L1 IHC 22C3 pharmDx by one trained pathologist. PD-L1 was measured using the combined positive score (CPS) by the pathologist using standard cutoffs (HNSCC, ≥1; UC and ESCC, ≥10). After PD-L1 status was determined using the LDT and PD-L1 IHC 22C3 pharmDx, the agreement between both assays was measured. Results: Samples from 327 patients with HNSCC (n = 126), UC (n = 121), and ESCC (n = 80) were evaluated for this study. The pan-tumor intraclass correlation coefficient (ICC) of PD-L1 CPS as a continuous variable was 0.96 (95% CI, 0.95-0.97); Spearman correlation was 0.95. Among patients with ESCC, ICC was 0.92 (95% CI, 0.88-0.95) and Spearman correlation was 0.89. The clinical interpretation of PD-L1 status (CPS ≥10) for ESCC samples using the 22C3 antibody LDT on the BenchMark XT platform and PD-L1 IHC 22C3 pharmDx resulted in a negative percentage agreement of 92% (95% CI, 80-97), a positive percentage agreement of 88% (95% CI, 74-95), and an overall percentage agreement of 90% (95% CI, 81-95). Conclusions: The 22C3 antibody-based LDT on the BenchMark XT platform demonstrated high concordance with the FDA-approved PD-L1 IHC 22C3 pharmDx across tumor types and in patients with ESCC alone. These findings suggest the comparability of PD-L1 IHC 22C3 pharmDx with an LDT based on the 22C3 antibody across several tumor types. This analysis will be expanded to include additional indications for inclusion in the presentation. Citation Format: Gilad W. Vainer, Ghadeer Zatara, Lingkang Huang, Kenneth Emancipator, Shanthy Nuti. Analytical comparison of a PD-L1 22C3 antibody LDT protocol on the BenchMark XT and PD-L1 IHC 22C3 pharmDx: Analysis of pan-tumor and esophageal cancer samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 503.

Abstract 951: Evolution of antibody titers, growth factor levels and in vitro activity in the sera of patients enrolled in the EPICAL trial of afatinib combined with anti-EGF vaccination

Abstract Background: We have recently demonstrated that antibodies generated by vaccination (anti-EGFVacAbs) potentiate the effects of EGFR TKIs in epidermal growth factor receptor mutant (EGFR-mut) non-small cell lung cancer (NSCLC) cells growing in vitro and prevent the emergence of resistance to EGFRTKIs (1). Based on these preclinical results we have started the Epical Phase Ib clinical trial(NCT03623750), testing anti-EGF vaccination in combination with EGFR TKI in advanced EGFR-mut NSCLC patients. Methods: The EPICAL trial is a Multicenter, Open-Label, Exploratory Phase Ib Clinical Study in which 23 patients have been enrolled. Anti-EGF VacAbs is a vaccine for intramuscular administration that is designed to be used in conjunction with standard of care treatment which, in this study, is afatinib. Blood samples have been collected at baseline and every three months and sent to a central laboratory. The presence of EGFR mutations has been determined on purified DNA by 5′-nuclease real-time PCR (Taqman®) assay in presence of PNA. All the serum samples have been analyzed by ELISA to determine the levels of EGF, TGFα, HGF and GAS6, together with anti-EGF antibody titers. Sera of patients were added to EGFR-mutant cell lines growing in vitro and Western blot was used to analyze EGFR, AKT andERK activation. Results: Median EGF levels in the sera of enrolled patients was 179.5 pg/mL at baseline and no anti-EGFantibodies were detected. Three months after first immunization, median serum EGF levels decreased to30.8 pg/mL (p=0.0008) while the anti-EGF vaccination titers increased to 1:6000 (p=0.0012). Anti-EGF titers remained high and EGF levels low in the patient's sera for the duration of the trial. Regarding serum TGFα and HGF levels baseline were 19.4 pg/mL and 861.2 pg/mL, respectively, and after three months dropped to 7.9 pg/mL (p=0.0037) and 341.3 pg/mL (p=0.0259). In EGFR-mutant cell lines in culture, the activation of the EGFR, AKT or ERK was abrogated by the sera of immunized patients. Conclusions: Anti-EGF vaccination induces high anti-EGF antibody titers and effectively reducing the levels of EGF and other growth factors in the blood of advanced NSCLC patients. 1J Thorac Oncol. 2018 Sep;13(9):1324-1337. Citation Format: Silvia Garcia-Roman, Jordi Codony, Miguel Angel Molina-Vila, Nuria Jordana-Ariza, Beatriz Garcia, Monica Garzon, Clara Mayo de las Casas, Maria Jose Catalan, Andres Aguilar, Santiago Viteri, Andres F. Cardona, Delvys Rodríguez, Manuel Cobo, Noemi Reguart, Erik d'Hondt, Rafael Rosell. Evolution of antibody titers, growth factor levels and in vitro activity in the sera of patients enrolled in the EPICAL trial of afatinib combined with anti-EGF vaccination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 951.

Commemorating the Silver Anniversary of the International Association for the Study of Lung Cancer International Workshop on Intrathoracic Staging

Commemorating the Silver Anniversary of the International Association for the Study of Lung Cancer International Workshop on Intrathoracic Staging

Development of Delayed Paraneoplastic ACTH Syndrome in Small Cell Lung Carcinoma

Background: Paraneoplastic/ectopic ACTH syndrome (EAS) is a rare but well-recognized syndrome in small cell lung carcinoma (SCLC), occurring in 1-5% of cases (1) and most often at diagnosis. We present a patient with SCLC who developed paraneoplastic ACTH syndrome 9 months after initiation of treatment. Case: A 73 year old female with long history of smoking and COPD (on home O2) and SCLC seen during hospitalization with severe muscle cramps, generalized weakness, hypertension and hypokalemia. Eleven months prior, she was diagnosed with SCLC after presenting with left superior mediastinum, supraclavicular and neck lymphadenopathy. She received 4 cycles of chemotherapy and immune checkpoint inhibitor (ICI) therapy (atezolizumab) was also initiated and continued throughout. Good response to therapy occurred until nine months post initiation, when relapse in same regions was identified on repeat PETCT. Physical examination revealed new onset resistant hypertension up to 240/120mmHg, and extensive bilateral lower extremity edema. Labs showed hypokalemia of 2.3 mmol/l and metabolic alkalosis with serum bicarbonate 43 mmol/l. Further investigations showed a random cortisol of 97.1 ug/dl with repeat of 175.9 ug/dl the following AM. ACTH was 374.1pg/ml. TSH was 0.25 uU/ml with low normal T4 and T3. Pituitary MRI showed no evidence of hypophysitis or enlargement. Repeat biopsy of cervical lymph node was unchanged from initial biopsy with two notable differences: morphology showed a “more organized, trabecular pattern” and MIB-1 staining had declined from 70-80% to 20%, and tumor cells stained positive for ACTH. She did not respond to octreotide, but did respond to ketoconazole (hypokalemia, edema improved and cortisol levels decreased to 24.2 ug/dl). However, hepatotoxicity occurred and thus it was discontinued with rapid rise of cortisol. As she was not a candidate for bilateral adrenalectomy, we started metyrapone with lowering of cortisol levels within 4 doses. However, new cavitary lesions on chest CT developed with concern for disseminated fungal infection. Patient elected for hospice and passed away the following day. Conclusion: We present an unusual case of paraneoplastic ACTH syndrome that developed after immunotherapy in SCLC. In summary, the relapse of SCLC while on immune therapy was associated pathologically by differentiation into a neuroendocrine tumor type and biochemically by a considerable ACTH production. We conclude that ACTH production with subsequent severe hypercortisolism causing immunosuppression may be a novel mechanism by which SCLC can evade immunotherapy.Reference: (1) Nagy-Mignotte H, Shestaeva O, Moro-Sibilot D et al. Prognostic impact of paraneoplastic cushing’s syndrome in small-cell lung cancer. J Thorac Oncol. 2014 Apr,9.

48-Year-Old Woman With Dyspnea and Chest Pain

48-Year-Old Woman With Dyspnea and Chest Pain

ES25.04 Multiple Pulmonary Lesions: Metastasis vs Multiple Primaries, From Martini's Criteria to Molecular Profiling

ES25.04 Multiple Pulmonary Lesions: Metastasis vs Multiple Primaries, From Martini's Criteria to Molecular Profiling

ES28.01 Biology of KRAS Targeting Agents

ES28.01 Biology of KRAS Targeting Agents

ES17.03 Updates in Squamous Cell Carcinoma and Neuroendocrine Tumors of the Lung

ES17.03 Updates in Squamous Cell Carcinoma and Neuroendocrine Tumors of the Lung

P76.27 ORCHARD: A Biomarker-Directed Phase 2 Platform Study in pts with Advanced EGFRm NSCLC Progressing on First-Line Osimertinib

Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in EGFRm advanced NSCLC, including central nervous system metastases. Most patients’ (pts) tumors develop resistance to osimertinib through secondary EGFR mutations (including C797S, G724S and L718V/Q) and off-target genomic alterations (including MET amplification and gene fusions). Data suggest that off-target alterations such as ALK and RET fusions may be resistance mechanisms to first-line osimertinib in some pts (each <5%). The ORCHARD study (NCT03944772) aims to better characterize resistance mechanisms to first-line osimertinib, and evaluate post-progression treatments. The flexible, platform-based design allows for new cohorts and treatment arms, for broader exploration of targeting resistance mechanisms. Previously presented: WCLC 2019 (Yu H, et al. J Thorac Oncol;14[10 suppl]:S647). In this open-label, multicenter, multidrug, biomarker-directed Phase 2 platform-based study (Figure), adult pts with locally advanced/metastatic EGFRm NSCLC whose disease progressed on first-line osimertinib are eligible. Treatment is assigned per molecular characterization of a mandatory tissue biopsy from a progressing lesion, analyzed by next-generation sequencing (Foundation Medicine Inc.). The protocol has recently been amended: Group A now includes treatment arms for pts with ALK/RET rearrangements, who will receive osimertinib plus alectinib/selpercatinib, respectively. The ‘MET alterations’ arm has been expanded from MET-amplification to also include MET exon 14 skipping, and the ‘EGFR alterations’ arm has been expanded from EGFR-amplification to also include mutations at the EGFR L718/G724 residue, or insertion in EGFR exon 20. Group B encompasses pts with no identifiable resistance mechanism; Group C is observational, for pts whose tumors harbor resistance mechanisms not currently addressed within the study. Tumor assessments (RECIST 1.1) will be performed every 6 weeks for 24 weeks, and every 9 weeks thereafter until disease progression or treatment discontinuation. Interim analyses will be performed on the first 16 pts in each cohort who have had the opportunity for two post-baseline RECIST assessments; individual cohorts may be stopped (if there is <10% probability for objective response rate [ORR] to be above target value [45%, equaling ≤4 of the 16 pts with confirmed responses]), or expanded to 30–40 pts for further evaluation. Primary endpoint: confirmed ORR (investigator assessed); secondary endpoints include: progression-free survival, duration of response, overall survival, and pharmacokinetics. Safety will also be reported. A summary of the observed genomic landscape during enrolment will be presented. osimertinib, non-small cell lung cancer, resistance

ES12.02 Defining High Risk

ES12.02 Defining High Risk

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RTwith passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

Systematic Review of Neoadjuvant Immunotherapy for Patients With Non–Small Cell Lung Cancer

There is a paucity of robust clinical evidence for the role of neoadjuvant immunotherapy in patients with resectable non-small cell lung cancer. The primary aim of the study was to identify the available data on the feasibility, safety and efficacy of neoadjuvant immunotherapy. A systematic review was conducted using electronic databases. Relevant studies were identified according to predefined selection criteria. Five relevant publications on 4 completed trials were identified. In most studies, >90% of patients were able to undergo surgery within the planned timeframe after neoadjuvant immunotherapy. There was a high incidence of open thoracotomy procedures, either planned or converted from a planned minimally invasive approach. Mortality ranged from 0 to 5%, but none of the reported deaths were considered directly treatment-related. Morbidities were reported according to adverse events related to neoadjuvant systemic therapy, and postoperative surgical complications. Survival outcomes were limited due to short follow-up periods. Major pathologic response ranged from 40.5 to 56.7%, whilst complete pathologic response of the primary tumor ranged from 15 to 33%. Radiological responses were reported according to RECIST criteria and fluorodeoxyglucose-avidity. This systematic review reported safe perioperative outcomes of patients who underwent resection following neoadjuvant immunotherapy. However, there was a relatively high incidence of open thoracotomy procedures, partly due to the technical challenges associated with increased fibrosis and inflammation of tissue, as well as the more advanced stages of disease in patients enrolled in the studies. Future studies should focus on identifying predictors of pathological response.

Scoping the Problem

Scoping the Problem