Search

INTRODUCTION: Immune checkpoint inhibitors (ICI) have been approved for patients with clear cell renal cell carcinoma (ccRCC), but not all patients benefit from ICI. One reason is the tumor microenvironment (TME) that has substantial influence on patient's prognosis and therapy response. Thus, we comprehensively analyzed the TME of ccRCC regarding prognostic and predictive properties. METHODS: Tumor-infiltrating CD3-positive T-cells, CD8-positive cytotoxic T-lymphocytes (CTLs), regulatory T-cells, B-cells, plasma cells, macrophages, granulocytes, programmed cell death receptor 1 (PD-1), and its ligand PD-L1 were examined in a large hospital-based series of ccRCC with long-term follow-up information (n = 756) and in another patient collective with information on response to nivolumab therapy (n = 8). Tissue microarray technique and digital image analysis were used. Relationship between immune cell infiltration and tumor characteristics, cancer-specific survival (CSS), or response to ICI was examined. RESULTS: Univariate survival analysis revealed that increased tumor-infiltrating B-cells, T-cells, and PD-1-positive cells were significantly associated with favorable CSS and high levels of intratumoral granulocytes, macrophages, cytotoxic T-cells, and PD-L1 significantly with poor CSS. High CTL or B-cell infiltration and high PD-L1 expression of ccRCC tumor cells qualified as independent prognostic biomarkers for patients' CSS. Significantly higher densities of intratumoral T-cells, CTLs, and PD-1-positive immune cells were observed in ccRCC with response to ICI compared with patients with mixed or no response (CD3: p = 0.003; CD8: p = 0.006; PD-1: p = 0.01). DISCUSSION: This study shows that subsets of tumor-infiltrating leukocytes in the TME and also PD-1/PD-L1 provide prognostic and predictive information for patients with ccRCC. Keywords: Renal cell carcinoma, Immune cell, Checkpoint inhibitor, Biomarker

TPS9157 Background: Epidermal growth factor receptor (EGFR) – mutated non-small cell lung cancer (NSCLC) is susceptible to EGFR targeting tyrosine kinase inhibitors (TKI), such as the third generation TKI osimertinib. However, response rate and duration vary between patients. Among others, the specific subtype of EGFR-mutation, its co-occurrence with other genetic alterations, and the detection of phosphorylated EGFR (pEGFR) in the plasma, and its clearance upon treatment were previously identified as markers that predict therapy response. A high proportion of patients with early (3-6 weeks after start) pEGFR clearance from plasma show impressive survival upon single-agent TKI. However, failure to achieve early clearance upon Osimertinib is associated with unfavorable outcome. For these patients, treatment concepts are lacking. Here, we report about the initiation of a clinical trial that evaluates the combination of EGFR-directed TKI and platinum-based chemotherapy as an early treatment escalation strategy for this high-risk patient population. Methods: PACE is a prospective multicenter single-arm investigator-initiated phase II trial. Patients with NSCLC harboring L858R or del19 EGFR mutation, who are treated with first-line Osimertinib are subjected to liquid biopsy-based early response assessment three weeks after start of therapy. Failure to clear pEGFR from plasma at this time point triggers treatment escalation with the addition of platinum-based doublet chemotherapy to the Osimertinib treatment. The primary outcome measure of the trial is progression-free survival (PFS), with the objective to assess the efficacy of biomarker-driven escalation of osimertinib therapy with a combination platinum-based regimen. Secondary outcome measures are the overall response rate (ORR), overall survival (OS), and the Quality of life (QLQ-C30, CTCAE-PROs) of the treated patients. In exploratory analyses, we will assess whether specific patterns of co-mutations are associated with early treatment failure (upon TKI) and pEGFR persistence. Fig. 1 illustrates the trial concept. A sample of 46 subjects achieves 80% power at a 0.05 significance level to detect a PFS of 14.4 months in the experimental treatment group when the PFS of the historic control group is 9.1 months; a total of 400 patients need to be screened within the national Network Genomic Medicine. Enrollment started in 12/2021. The clinical trial is supported by AstraZeneca and Guardant. EudraCT registration number: 2019-004757-88 .

2579 Background: In preclinical studies, the combination of anti-VEGF/Ang2 and anti-PD-1 therapy has been shown to promote an immunopermissive state, which is supportive of T-cell-mediated tumor cell destruction. BI 836880 is a humanized bispecific nanobody that targets VEGF and Ang2, and ezabenlimab (BI 754091) is an anti-PD-1 antibody. Phase I studies investigating each as monotherapies have reported safety and preliminary antitumor activity. This ongoing Phase Ib study is evaluating the combination of BI 836880 and ezabenlimab in pts with advanced solid tumors. In Part 1 (dose escalation), the combination was feasible in pts with advanced NSCLC, with a recommended Phase II dose (RP2D) of BI 836880 720 mg + ezabenlimab 240 mg IV q3w. Here, we report updated results from Part 2 (expansion phase), which is assessing the antitumor activity and safety of the RP2D. Methods: Seven cohorts are currently recruiting pts in Part 2: metastatic (m) NSCLC after checkpoint inhibitor (CPI) monotherapy (Cohort A); mNSCLC after chemotherapy (CT) + CPI (Cohort B); mSCLC after CT ± CPI (Cohort C); 1st and 2nd recurrences of glioblastoma (GBM; Cohort D); immunotherapy-resistant m-melanoma (Cohort E); hepatocellular carcinoma (HCC) after prior sorafenib or lenvatinib ± CPI (Cohort F); and previously untreated/unresectable HCC (Cohort G). Primary endpoint is objective response rate (complete response + partial response [PR]). Results: As of January 2021, 196 pts have received BI 836880 plus ezabenlimab (14 in Part 1, 182 in Part 2 [Cohort A, 26; B, 30; C, 19; D, 31; E, 32; F, 28; G, 16]). 134 (68%) pts were male, median age was 63 years and 102 (52%) had prior CPI use. Any grade and ≥G3 adverse events (AEs; any cause) were reported by 160 (82%) and 62 (32%) pts, most commonly (all%/≥G3%) hypertension (20/8), asthenia (20/3), diarrhea, decreased appetite, and nausea (all 11/1). 95 (48%) pts had a drug-related AE, most commonly hypertension and asthenia (both 11%). 6 pts had a G4 AE (non-related: hyperkalemia + cardiac arrest, laryngospasm, gastrointestinal perforation; drug-related: anaphylactic reaction, acute pancreatitis, transaminases increased); 8 pts had a G5 AE (non-related: general physical health deterioration, epilepsy, hemoptysis, cardio-respiratory arrest, hepatic failure, intracranial hemorrhage, COVID-19 pneumonia; drug-related tracheal hemorrhage). 30 (15%) pts had immune-related AEs (3% ≥G3), including hypothyroidism (3%). 11 (6%) pts had an AE leading to discontinuation. Overall, 145 pts were evaluable for response: 9 pts achieved confirmed PR (2 pts in Part 1 and 7 in Part 2 [NSCLC, n = 3; SCLC, n = 1; GBM, n = 1; melanoma, n = 1; and 2nd-line HCC, n = 1]), 87 pts had stable disease and 49 pts had progressive disease. 111 pts remain on treatment. Conclusions: BI 836880 plus ezabenlimab had a manageable safety profile. The combination showed preliminary antitumor activity in a range of tumor types. Clinical trial information: NCT03468426.

TPS8585 Background: Non-small cell lung cancer (NSCLC) is the most common cause of cancer death worldwide highlighting the importance of improving current therapeutic options. In particular, elderly and frail patients are not only underrepresented in clinical trials, but also frequently do not receive standard treatment regimens due to comorbidities. For example, patients with unresectable stage III NSCLC who are unfit for chemotherapy (CHT) do not benefit from the recent seminal therapy algorithm change for this disease, i.e. consolidation therapy with the immune checkpoint inhibitor (ICI) durvalumab after combined radiochemotherapy (RChT). Instead, these patients are treated with radiotherapy only, raising the serious concern of undertreatment. This issue is addressed by the TRADE-hypo clinical trial that investigates a novel therapy option for NSCLC stage III patients not capable of receiving CHT. To this end, thoracic radiotherapy (TRT) is administered together with durvalumab, employing the synergism created by the combination of restoring anti-tumor immune response by the ICI with the induction of immunogenicity by irradiation. The latter effect has been suggested to be further boosted by hypofractionated radiotherapy, which could also be more practicable for the patient. Taken these considerations into account, the TRADE-hypo trial addresses safety and efficacy of durvalumab therapy combined with either conventional or hypofractionated TRT. Methods: The TRADE-hypo trial is a prospective, randomized, open-label, multicentric phase II trial. Eligible patients are diagnosed with unresectable stage III NSCLC and not capable of receiving sequential RChT due to high vulnerability as reflected by a poor performance status (ECOG 2 or ECOG1 and CCI≥ 1) and/or high age (≥ 70)]. Two treatment groups are evaluated: Both receive durvalumab (1,5000 mg, Q4W) for up to 12 months. In the CON-group this is combined with conventionally fractionated TRT (30 x 2 Gy), while in the HYPO-group patients are treated with hypofractionated TRT (20 x 2.75 Gy). In the HYPO-arm, a safety stop-and-go lead-in phase precedes full enrollment. Here, patients are closely monitored with regard to toxicity (i.e., pneumonitis grade ≥ 3 within 8 weeks after TRT) in small cohorts of 6. The primary objective of the trial is safety and tolerability. As a primary efficacy endpoint, the objective response rate after 3 months will be evaluated. Further endpoints are additional parameters of safety and efficacy, as well as the comprehensive collection of biomaterials to be analyzed regarding treatment-induced changes and potential novel biomarkers. As of February 10, 2021, 9 patients of planned 88 patients have been enrolled in the TRADE-hypo trial. Clinical trial information: NCT04351256.

9036 Background: The nNGM centralizes molecular diagnostics, treatment recommendations and follow-up reporting in NSCLC in Germany. Uncommon EGFR mutations pose a clinical challenge because they comprise a heterogenous group and analyses of treatment outcome are still scarce. Here, we analyzed follow-up data of patients with rare EGFR mutations and performed functional characterization of recurrent mutations with unknown function. Methods: This multicenter, retrospective analysis of uncommon EGFR mutations (excluding L858R-, T790M mutations and exon 19 deletions) includes stage IV patients with NSCLC from 12 nNGM centers. We categorized EGFR-mutations into 3 groups: uncommon EGFR mutations with known driver function, for instance E709X, G719X, S768I and L861Q (group 1), exon 20 insertions (group 2) and all other very rare mutations (group 3). Functional characterization of unknown mutations was performed by insertion mutagenesis in Ba/F3 cells and monitoring of growth factor-independent proliferation. Results: In total, 834 cases with uncommon EGFR mutations were reported. Follow-up data after EGFR-TKI (Erlotinib, Gefitinib, Afatinib and Osimertinib), chemotherapy and/or mono-PD(L)1 blockade was available for 252 patients. Mean progression free survival (mPFS) on EGFR-TKIs vs. chemotherapy was 6.6 months vs. 5.0 months (HR 0.54, 95%CI 0.35 to 0.81, P =.003) in group 1 (n = 84), and 6.7 months vs. 3.4 months (HR 0.66, 95%CI 0.47 to 0.92, P =.015) in group 3 (n = 104). Mono-anti-PD(L1) blockade was not superior to chemotherapy (group 1, mPFS 3.0 months, HR 1.32, 95% 0.55 – 3.15, P =.535 and group3, mPFS 4.3 months, HR 1.02, 95% CI 0.64 – 1.62, P = 0.951). Exon 20 insertions (group 2, n = 63) did not benefit from EGFR-TKIs or anti-PD(L1) blockade vs. chemotherapy. Overall survival (OS) analysis (n = 218) following chemotherapy (56%) or EGFR-TKI treatment (44%) showed median OS (mOS) of 18.0 months vs. 13.9 months in patients treated with EGFR-TKI and chemotherapy, respectively in group 1 (HR 0.97, 95%CI 0.54 to 1.75, P =.929). In group 3 patients treated with EGFR-TKI and chemotherapy had a mOS of 35.4 months vs. 12.0 months, respectively (HR 0.59, 95%CI 0.35 to 1.01, P =.056). In the Ba/F3 system we could identify 8 recurrent driver and 12 non-driver mutations with a clinically applicable assay turnaround time of 4 weeks to inform clinical decision-making in the future. Conclusions: This real-world dataset confirms that patients with group 1(uncommon) EGFR mutations benefit from EGFR-TKIs and indicates that mono-anti PD(L)1 blockade is not superior to chemotherapy. Furthermore, patients with very rare EGFR mutations (group 3) also experienced a PFS benefit from EGFR-TKI compared to chemotherapy while immune therapy was not beneficial.

The significant process parameter variations occurring during fabrication of high performance sequential circuits, such as microprocessors, are posing relevant uncertainties on the power that such circuits will consume in the field, while executing workloads typical for the diverse products they are oriented to (e.g., cellular phones, notebooks, servers, etc). On the other hand, different kinds of products have different constraints on the maximal power that could be consumed during the execution of typical workloads, due to diverse needs in terms of charge autonomy, heat dissipation, etc. Consequently, the power that will be consumed by microprocessors during the execution of typical workloads in the field needs to be accurately characterized at the end of fabrication. Such a power consumption characterization (hereinafter referred to as “power binning”), will enable to classify microprocessors in “power bins”, each one containing microprocessors suitable for different kinds of products, thus enabling to introduce them all into the market for different kinds of products. Based on these considerations, in this paper we propose an approach to characterize accurately at the end of fabrication, and at low-cost (in terms of characterization time), the power that microprocessors will consume in the in-field during the execution of workloads typical for different kinds of products. Our approach exploits scan-based Logic Built-In Self-Test (LBIST) to apply to microprocessors’ sequential blocks test vectors that induce on their internal nodes an activity factor (AF) similar to that experienced during the in-field execution of workloads typical for different kinds of products, thus enabling to perform power binning by simply measuring their consumed power. Our approach enables to scale the AF from 0 percent up to 97.6 percent (on average for the considered benchmark circuits) compared to conventional LBIST, with a granularity of the 2 percent, thus enabling to emulate accurately the AF induced by workloads typical of a wide range of products. We propose a hardware implementation for our approach requiring a limited area overhead (lower than 3 percent) over conventional LBIST.

9566 Background: Preclinical studies show that combining anti-VEGF/Ang2 with anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumor cell destruction. BI 836880 is a humanized bispecific nanobody that targets VEGF and Ang2, and BI 754091 is an anti-PD-1 antibody. Each has shown manageable safety and preliminary activity as monotherapy. Here, we report initial results from a Phase Ib study assessing BI 836880 in combination with BI 754091. Methods: In Part 1 (dose escalation), pts with locally advanced or metastatic (m) non-squamous NSCLC who progressed during/after completion of ≥2 cycles of platinum-based chemotherapy (CT) ± a checkpoint inhibitor (CPI) were enrolled. Pts received BI 836880 (cohorts of 360, 500 and 720 mg intravenously [iv] 3-weekly [q3w]) plus fixed-dose BI 754091 (240 mg iv q3w). Dose escalation was guided by Bayesian logistic regression models with overdose control. Primary endpoint in Part 1 was maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), based on dose-limiting toxicities (DLTs) in Cycle 1. Initial safety and efficacy results of Part 1 are reported here. Part 2 will assess safety and efficacy in 6 expansion cohorts: mNSCLC after CPI monotherapy; mNSCLC after CT + CPI; mSCLC after CT ± CPI; immunotherapy-resistant m-melanoma; recurrent glioblastoma after 1st-line CT; and hepatocellular carcinoma after prior sorafenib or lenvatinib ± subsequent CPI. Results: 12 pts received BI 836880 plus BI 754091 (8 male; median age 59.5 years; 8 had received prior CPI). 4 pts remain on treatment (including 1 treated for 15 cycles). 1 pt had a DLT during Cycle 1 (360 mg; G3 pulmonary embolism). All pts experienced an adverse event (AE; any-cause; safety data cut-off Nov 2019), most commonly (all%/G3%) hypertension (58/25), vomiting (42/0), nausea (33/0), and asthenia (33/0). Hypertension was transient. No G4 AEs were reported; one G5 AE occurred (general physical health deterioration). 5 pts had immune-related AEs (G2 hypothyroidism in 2 pts; G2 pruritus, G1 papular rash, and G2 vomiting). To date (Jan 2020), 2 pts have achieved partial response; 1 pt (500 mg dose; CPI-naïve) had 58% target lesion reduction, and 1 (720 mg; prior CPI) had 35% target lesion reduction. 8 pts had stable disease. Conclusions: MTD/RP2D was BI 836880 720 mg plus BI 754091 240 mg q3w. The combination had a manageable safety profile, and preliminary anti-tumor activity was observed. Expansion cohorts are ongoing. Equal contribution: JA and BH Clinical trial information: NCT03468426 .

69 Background: HER2 is overexpressed in many solid tumors and is a validated therapeutic target. GBR 1302 is a HER2xCD3 bispecific antibody engineered (using Glenmark’s BEAT® platform) to direct T-cells to HER2-expressing tumor cells. GBR1302-101 (NCT02829372) is an ongoing, multicenter, open-label, first-in-human study of GBR 1302 in subjects with HER2-positive cancers to evaluate the safety, tolerability, and preliminary efficacy of GBR 1302, and to elucidate the mechanism(s) by which it redirects T-cells to tumor and enhances cytolytic activity of cytotoxic T-cells. Methods: Adults with progressive HER2-positive solid tumors with no available standard or curative treatment receive intravenous GBR 1302 on Day 1 and Day 15 in 28-day treatment cycles at escalating dose levels, starting at 1 ng/kg. The first 4 cohorts consist of a single subject; subsequent cohorts enroll using a 3+3 design. The primary and secondary efficacy and safety endpoints of this trial will be reported at the end of the study. Preliminary pharmacodynamic (PD) data are reported for cellular biomarkers and cytokines as assessed by FACS and ELISA in peripheral blood. Results: Beginning at 30 ng/kg dosing of GBR 1302 (Cohort 4), numbers of peripheral blood CD3, CD4, and CD8 positive T-cell populations decreased within 6 hours of initiating administration, but recovered to levels at or above baseline by 48 hours. A parallel, transient increase was observed in peripheral blood cytokines (IL-2, IL-6, IL-10, IFN-γ, TNF-α). At doses greater than 30 ng/kg, more pronounced cytokine increases were observed, which normalized at 12 hours. At the highest dose level for which data are available (n = 8 subjects; Cohort 5), changes from baseline in cytokine expression at ~340 hours were greater by ~60-fold for IL-6, ~30-fold for IL-2, ~3-fold for IFN-γ, ~5-fold for TNF-α, and ~18-fold for IL-10. Two subjects treated at 100 ng/kg experienced Grade 1 cytokine release syndrome, evidenced by short-lived fever spikes. Dose escalation is ongoing. Conclusions: Preliminary PD data indicate changes in peripheral T-cell populations and inflammatory cytokines following GBR 1302 treatment. Clinical trial information: NCT02829372.

e20522Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation may contribute to primary and secondary resistance to platinum (Pt)-based chemotherapy (CT) in sqNSCLC. The pan-PI3K inhibi...