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Purpose:Non–small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. A membrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo–activated NK cells in patients with NSCLC after radiochemotherapy (RCT).Patients and Methods:Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60–70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses.Results:The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%–90%] for the INT arm and 33% (95% CI, 5%–68%) for the CTRL arm (P = 0.36, 1-sided log-rank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood.Conclusions:Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.

Lung cancer is most common in older patients; despite this, older patients are historically under-represented in clinical studies. Here we present data from GIDEON, a study undertaken in Germany in patients with epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) receiving first-line afatinib. GIDEON enrolled a high proportion of patients aged ≥70 years, providing an opportunity to study afatinib use in older patients.In GIDEON (NCT02047903), a prospective non-interventional study, patients with EGFRm + NSCLC received first-line afatinib in routine clinical practice until disease progression, death or intolerable adverse events. Key objectives were twelve-month progression-free survival (PFS) rate and objective response rate (ORR). Overall survival (OS) and safety were also assessed. This post hoc analysis explores outcomes of patients grouped by age (≥70 and 70 years).In the 152 patients enrolled in GIDEON (69.7% female, 64.5%/22.4%/13.2% with Del19/L858R/other exon 18-21 mutations, 33.6% with brain metastases), the median age was 67 years (range 38-89) and 43.4% were aged ≥70 years. In the ≥70 years age group and the70 years age group, twelve-month PFS rate was 58.9% and 43.9%, median PFS was 17.2 months and 10.6 months, ORR was 72.0% and 76.5%, twelve-month OS rate was 79.1% and 79.2%, 24-month OS rate was 52.0% and 61.7%, and median OS was 30.4 months and 27.4 months, respectively. In the ≥70 years age group and the70 years age group, grade ≥ 3 adverse drug reactions (ADRs) were observed in 34.8% and 40.7% of patients, respectively; the most common were diarrhea (13.6% and 14.0%), acneiform dermatitis (7.6% and 7.0%), stomatitis (1.5% and 4.7%) and maculopapular rash (1.5% and 4.7%).Patients with EGFRm + NSCLC aged ≥70 years showed clinical benefit from first-line afatinib with no unexpected safety signals, supporting the use of afatinib in this setting.

Background Membrane heat shock protein 70 (mHsp70) is indicative of high-risk tumors and serves as a tumor-specific target for natural killer (NK) cells stimulated with Hsp70 peptide (TKD) and Interleukin(IL)-2. Radiochemotherapy (RCT), mHsp70-targeting NK cells, and programmed death(PD)-1 inhibition were combined to improve the efficacy of tumor-specific immune cells in a non-small cell lung carcinoma (NSCLC) patient. Patient Following simultaneous RCT (64.8 Gy), a patient with inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated with 4 cycles of autologous ex vivo TKD/IL-2-activated NK cells and the PD-1 antibody nivolumab as a second-line therapy. Blood samples were taken for immunophenotyping during the course of therapy. Results Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3−/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3−/CD56bright to CD3−/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood. Conclusion A combined therapy consisting of RCT, mHsp70-targeting NK cells, and PD-1 antibody inhibition is well tolerated, induces anti-tumor immunity, and results in long-term tumor control in one patient with advanced NSCLC. Further, randomized studies are necessary to confirm the efficacy of this combination therapy.

Background: Lung cancer is a leading cause of cancer-related death in Germany and worldwide. Non-small cell lung cancer (NSCLC) comprises ~80% of lung cancer diagnoses; in White patients, around 10% of NSCLC cases are epidermal growth factor receptor mutation-positive ( EGFRm+). Head-to-head clinical trials have demonstrated superior efficacy with second-/third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) versus first-generation EGFR TKIs in EGFRm+ NSCLC. Data from routine clinical practice are necessary to confirm that clinical trial findings are transferable to real-world populations. Methods: In NCT02047903, a prospective non-interventional study in Germany, patients with EGFRm+ NSCLC received first-line afatinib until disease progression or intolerable adverse events. Key objectives were progression-free survival (PFS) rate at 12 months, objective response rate (ORR) and overall survival (OS). Safety/tolerability was also assessed. Results: Of 152 patients, 106 (69.7%) were female, 20 (13.1%) patients had an uncommon EGFR mutation and 51 patients (33.6%) had brain metastases. A starting dose of Conclusion: The results support clinical trial data for afatinib in routine clinical practice, including in patients generally excluded from clinical trials. Outcomes were positive in patients with uncommon EGFR mutations and in those with brain metastases. Treatment benefit was also seen in patients receiving a

Objectives: After decades of unsuccessful efforts in inhibiting KRAS, promising clinical data targeting the mutation subtype G12C emerge. Since little is known about outcome with standard treatment of patients with G12C mutated non-small cell lung cancer (NSCLC), we analyzed a large, representative, real-world cohort from Germany. Patients and methods: A total of 1039 patients with advanced KRAS-mutant or -wildtype NSCLC without druggable alterations have been recruited in the prospective, observational registry CRISP from 12/2015 to 06/2019 by 98 centers in Germany. Details on treatment, best response, and outcome were analyzed for patients with KRAS wildtype, G12C, and non-G12C mutations. Results: Within the study population, 160 (15.4 %) patients presented with KRAS G12C, 251 (24.2 %) with non-G12C mutations, 628 (60.4 %) with KRAS wildtype. High PD-L1 expression (Tumor Proportion Score, TPS > 50 %) was documented for 28.0 %, 43.5 %, and 28.9 % (wildtype, G12C, non-G12C) of the tested patients; 68.8 %, 89.3 %, and 87.7 % of the patients received first-line treatment combined with an immune checkpoint-inhibitor in 2019. TPS > 50 % vs. TPS < 1 % was associated with a significantly decreased risk of mortality in a multivariate Cox model (HR 0.39, 95 % CI 0.26−0.60, p=

Lung cancer is a leading cause of cancer-related death in Germany and worldwide. Non-small cell lung cancer (NSCLC) comprises ~80% of lung cancer diagnoses; in White patients, around 10% of NSCLC cases are epidermal growth factor receptor mutation-positive (In NCT02047903, a prospective non-interventional study in Germany, patients withOf 152 patients, 106 (69.7%) were female, 20 (13.1%) patients had an uncommonThe results support clinical trial data for afatinib in routine clinical practice, including in patients generally excluded from clinical trials. Outcomes were positive in patients with uncommon

Purpose: Non–small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. A membrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo–activated NK cells in patients with NSCLC after radiochemotherapy (RCT). Patients and Methods: Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60–70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses. Results: The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%–90%] for the INT arm and 33% (95% CI, 5%–68%) for the CTRL arm (P = 0.36, 1-sided log-rank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood. Conclusions: Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.

Analysis of scientific publications of recent years has shown the need to further study the development of man-made mineral deposits in Ukraine. The main reasons for development of man-made deposits were considered, and the basic requirements for mining man-made deposits were formed, including: efficiency increase of mining operations; reduction of negative environmental impact on the region and restoration of land after industrial activity. Technology that made it possible to group dumps based on their formation is analyzed, which allowed to form clusters. They allow to determine the optimal technology for the development of man-made deposits based on the type of minerals to be extracted and the method of its formation. As a result of the study, the algorithm of making decision on the choice of optimal technology for the development of man-made deposits based on graphical data was developed, taking into account the type of minerals to be extracted, depending on the structure of the deposit and the specific features of its formation.

Membrane-bound heat shock protein 70 (mHsp70) is indicative for high-risk tumors with negative prognosis but also serves as a target for NK cells that are stimulated with Hsp70 peptide TKD and low dose IL-2 (TKD/IL-2). Herein, the efficacy of ex vivo TKD/IL-2 activated, autologous NK cells was tested in a randomized, investigator initiated phase II clinical trial in patients with mHsp70 positive advanced stage NSCLC after radiochemotherapy (RCT, 60-70 Gy, platinum-based chemotherapy). The interventional (INT) group received 4 cycles TKD/IL-2 activated, autologous NK cells every 2-6 weeks subsequent to standard RCT and the control (CTRL) group received best supportive care. The primary objective of the study was to examine whether the adjuvant treatment of NSCLC patients with TKD/IL-2 activated NK cells is feasible and effective with respect to progression-free survival (PFS). Secondary objectives were the assessment of treatment and biological responses, toxicity, quality-of-life (QoL, QLQ-LC13). Eight patients were randomized into the INT and eight into the CTRL arm. None of the patients died between randomization and final tumor assessment 18 months after randomization. In the INT group one patient had complete response (CR), one patient partial response (PR), two patients stable disease (SD) and one patient progressive disease (PD) at the last documented visit, whereas in the CTRL group only 2 patients showed clinical responses (PR, SD) and five patients had PD. The clinical response of patients in the INT group appeared to be mediated by activated NK cells whereas in the CTRL group by CD8+ T cells. The NK cell therapy after RCT was well tolerated, no differences in QoL were observed between both study groups. Citation Format: Gabriele Multhoff, Stephanie E. Combs, Sophie Seier, Stefan Stangl, Wolfgang Sievert, Maxim Shevtsov, Christiane Blankenstein, Martin Hildebrandt, Konrad Kokowski, Matthias Hautmann, Hubert Hautmann, Claus Roedel, Rainer Fietkau, Rudolf M. Huber, Bernhard Haller, Christina Ertl, Michal Devecka, Robert Offner, Norbert Ahrens. Targeted Natural Killer (NK) cell based adoptive immunotherapy for the treatment of patients with non-small cell lung cancer (NSCLC) after radiochemotherapy - results of a randomized phase II clinical trial (NSCLC-TKD/IL-2) (Eudra-CT Number 2008-002130-30) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-076.

e21636 Background: Afatinib is an irreversible ErbB family blocker, which is approved for the treatment of advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. Here we report the final results of the prospective non-interventional study (NIS) GIDEON, which was initiated to investigate the efficacy and tolerability of afatinib in the daily clinical routine in Germany. Methods: EGFR-mutated NSCLC patients were treated with afatinib according to label until progression, death or discontinuation. Efficacy (progression-free survival (PFS) rate at 12 months, objective response rate, ORR; disease control rate, DCR; progression-free survival, PFS and overall survival, OS) was prospectively assessed by investigators. Data about tolerability were collected during routine treatment. Results: In total, 161 patients were enrolled at 41 sites in Germany, 152 patients received at least one dose of afatinib (treated set; TS) and 146 patients were treated according to the protocol (PPS). The majority of patients for the entire TS had exon 19 deletions (64.5%), followed by L858R point mut. (22.4%) and uncommon mut. (exon 18-21 point mut.; 13.1%). The primary objective was PFS-rate at 12 months, which was 50.2% in the PPS. Median PFS amounted to 12.2 months. ORR and DCR were 74.6% and 91.5% in the PPS, respectively. Median OS was 30.4 months with 1- and 2-year survival rates of 79.1% and 57.7%, respectively. Among pat. with uncommon EGFR-mut., the 12-months PFS rate was 40.2% with a mPFS of 10.7 months. ORR and DCR were 83.3% and 91.7%, respectively. The most frequent documented adverse drug reactions (ADRs) were diarrhea and rash/acne with 13.8% and 7.2% of grade 3 but no grade 4 or higher. Conclusions: Afatinib is a standard therapy for patients with activating EGFR mut. in Germany. The final results of this prospective NIS confirm the robust clinical data for afatinib in the clinical routine setting, including patients with uncommon exon 18-21 point mutations. Clinical trial information: NCT02047903.

Advanced stage NSCLC is a fatal disease with poor prognosis. Following radiochemotherapy (RCT) tumor progression occurs after 5.6 months in stage III NSCLC patients. We identified membrane heat shock protein 70 (mHsp70) as a biomarker for high-risk NSCLC. Furthermore, mHsp70 serves as a tumor-specific target for NK cells that had been stimulated with Hsp70-peptide (TKD) and IL-2. In this study, a patient with mHsp70 positive inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated for the first time with a combined therapy consisting of RCT (64.8 Gy), 4 cycles of mHsp70-targeting, autologous NK cells and PD-1 antibody, as a second-line therapy. Adoptive transfer of ex vivo Hsp70-activated NK cells after RCT combined with PD-1 inhibition was well tolerated and resulted in a superior OS. No viable tumor cells, but a massive immune cell infiltration of T and NK cells in fibrotic tissue were detected after therapy. Neither tumor progression nor distant metastases were detectable by CT-scanning 35 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell, CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood. In summary, a combined immunotherapy consisting of RCT, mHsp70-targeting NK cells and PD-1 antibody inhibition is well tolerated, induces anti-tumor immune responses and results in long-term tumor control in a patient with advanced NSCLC. Citation Format: Gabriele Multhoff, Konrad Kokowski, Martin Hildebrandt, Peter Vaupel, Stefan Stangl. Radiochemotherapy combined with NK cells followed by a second-line PD-1 inhibition in a patients with NSCLC stage IIIb induces long-term tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-016.

Introduction: Mucin 1, encoded by the MUC1 gene, is a tumor-associated antigen expressed on the surface of breast cancer cells. It would be of interest to see whether there is a naturally existing T cell immune response against mucin epitopes in cancer patients. Materials and Methods: Using tetramer and interferon-γ assays, the immune response to one MUC1 peptide epitope in the peripheral blood of breast cancer patients was quantified. The data were compared with the clinical course of the patients. Results: CD8+ T cells capable of recognizing the HLA-A*0201-restricted STAPPVHNV epitope were detected in 9 of 19 patients with a frequency ranging 0.01–0.082%. No significant difference was found between the occurrence of epitope-specific CD8+ T cells of patients with progressive disease and disease-free patients. However, all patients with stable disease showed a specific immune response, including both patients with the highest frequency. Conclusions: The results of this study provide further evidence that a natural specific cellular immune response against this mucin epitope exists in breast cancer patients.