Lungenkarzinom (inkl. Pleura) I

V288 Klinische Plattform zur Erforschung molekularer Testung, Behandlung und Krankheitsverlauf von Patienten mit Lungenkrebs (CRISP): Erste Real-World Evidence zu NSCLC Stadium II und III in Deutschland - AIO-TRK-0315
Wilfried Eberhardt, Essen, D

Background: CRISP is a non-interventional, prospective, multi-center clinical research platform whose aim is to understand the treatment reality of patients (pts) with lung carcinoma in Germany. Here we present first data of pts diagnosed with NSCLC in stages II or III (IIIB/C if treated with curative intent).

Methods: Between August 2018 and February 2020 around 100 sites in Germany recruited more than 800 pts diagnosed with NSCLC stage II/III. Basic demographic data, details about treatment reality, outcome and PRO data are collected and analyzed. Here we present first data on 715 pts followed until 30 June 2020.

Results: 25% of the pts were diagnosed with stage II (4% in stage IIA, 21% in stage IIB), and 68% with stage III disease (33% in stage IIIA, 34% in stage IIB/C). 51% of the tumors were adenocarcinomas. The median age at primary diagnosis was 65 years (38% women, 62% men), 83% of the pts had an ECOG 0/1. 80% of the pts presented with comorbidities; 47% had a Charlson comorbidity index of 0. 25% of the pts were current smokers; 43%, heavy ex-smokers, and 9% were never-smokers.

Most of the pts with tumors in stage II underwent surgery (84%, n=153) followed by adjuvant chemotherapy (CTx) (currently 67%, n=123). For pts with stage IIIA tumors the most frequent sequence of treatment was also surgery (56%, n=134) followed by adjuvant CTx (currently 37%, n=89). 24% (n=57) of the pts with stage IIIA received radiochemotherapy (RTCTx). For pts with stage IIIB/C tumors the most frequent treatment was RTCTx (n=101, 41 %); 35% (n=85) started with CTx, and 20% (n=50) had surgery (followed mostly by CTx, currently n=35, 14%).

67% (n=80) of pts with an inoperable stage III tumor who received RTCTx were tested for PD-L1 expression. 48 pts had a positive PD-L1 expression, which corresponds to 40% of all pts and 60% of the tested pts. 30 pts out of 41 eligible (best response CR/PR/SD) received consolidation therapy with durvalumab.

Conclusion: CRISP presents comprehensive current real-life data of patients with NSCLC in stage II or III covering all treatment settings in Germany. With longer follow-up outcome in routine care will be analyzed.


V631 Therapieansprechen von Patienten mit seltenen EGFR-Mutationen - eine retrospektive Analyse des nationalen Netzwerks Genomische Medizin (nNGM)
Melanie Janning, Mannheim, D

Background: Uncommon EGFR are estimated to occur in 1-2 % of patients with non-small cell lung cancer (NSCLC). They comprise a heterogenous group and present a clinical challenge because information about response to treatment is scarce. We present a retrospective analysis of response to systemic treatment in 265 NSCLC patients with uncommon EGFR mutations from the nNGM network. Method: Data were collected from 12 nNGM centers. EGFR-mutations (excluding single L858R-, T790M mutations and exon 19 deletions) were categorized into 3 groups: uncommon EGFR mutations with known driver function such as E709X, G719X, S768I and L861Q (group 1), exon 20 insertions (group 2) and all others very rare mutations (group 3). Progression free survival (PFS) was analyzed using Kaplan Meier plots and COX hazard proportional models.

Results: 58% of the patients were females, 91% had an adenocarcinoma and 57% were either current or former smokers. Median PFS (mPFS) for all analyzable treatments (all lines) was 6.6 months for EGFR- TKIs vs. 4.9 months for chemotherapy in group 1 (HR 0.54, 95%CI 0.35 to 0.81, P = .003, n=134) and 6.7 months vs. 3.5 months in group 3, respectively (HR 0.68, 95%CI 0.48 to 0.95, P = .024, n=169).

Afatinib (A) was the most frequently administered TKI in both groups (46% and 51% in group 1 and 3, respectively). The longest mPFS in group 1 was observed in patients treated with A (12.0 months). MPFS in group 1 was 3.8 months with erlotinib (E, 29%), 9.1 months with gefitinib (G, 16%) and 5.0 months with osimertinib (O, 10%, overall log rank 0.014]. Interestingly, in group 3 treatment with G was advantageous [5.9 months (A, 51%), 3.0 months (E, 16%), 16.0 months (G, 15%) and 6.8 months (O, 18%), overall log rank 0.095].
Mono-anti-PD(L1) blockade was not superior to chemotherapy in group 1 and 3 (group 1, mPFS 3.0 months, HR 1.32, 95% 0.55 - 3.15, P = .535; group3, mPFS 4.3 months, HR 1.04, 95% CI 0.65 - 1.68, P = 0.859).
Exon 20 insertions (group 2, n=115 treatments) did not benefit from EGFR-TKIs or anti-PD(L1) blockade in comparison to chemotherapy.

Conclusions: This real-world dataset confirms that patients with uncommon (group 1) and very rare EGFR mutations (group 3) benefit from EGFR-TKIs compared to chemotherapy. The comparison between the TKIs needs to be interpreted with caution due to small sample size. Altogether, the group of very rare EGFR mutations needs to be functionally characterized. This issue will be addressed by the nNGM consortium in the future.

V522 SAKK 16/14 - T-Zell-Rezeptor Repertoire: Ein neuer prädiktiver Faktor für das Ansprechen auf eine neoadjuvante Immuntherapie bei Patienten mit NSCLC im Stadium IIIA(N2)

Introduction: T-cell receptor (TCR) repertoire assessment in blood and tissue has emerged as a novel predictive marker for response to immune checkpoint inhibitor therapy in advanced stage cancers. However, its relevance and predictive significance in the setting of resectable stage IIIA(N2) non-small cell lung cancer (NSCLC) has yet to be demonstrated. Here, we performed TCR sequencing in patients from the phase 2 trial SAKK 16/14 undergoing neoadjuvant chemotherapy with three cycles of cisplatin/docetaxel followed by treatment with the PD-L1 antibody durvalumab.

Methods: A total of 127 peripheral blood samples and 67 formalin-fixed paraffin-embedded (FFPE) tissue samples were processed from 67 patients before and after neoadjuvant sequential chemo- immunotherapy treatment in the trial SAKK 16/14. Total RNA was extracted from peripheral blood and FFPE samples and used for TCR sequencing with the Oncomine TCR Beta-LR and SR Assays, respectively. TCR evenness, Shannon diversity, and TCR richness were calculated and correlated with the primary endpoint event-free survival (EFS) after 1 year, major pathological response (MPR), and nodal clearance. Association between TCR metrics and clinical outcome data were analyzed using Mann-Whitney-Wilcox test. Analysis was performed using R (R Core Team, 2014).

Results: TCR repertoire could be assessed in a total of 97 peripheral blood (47 pre- and 50 post- treatment) and 64 FFPE (15 pre- and 49 post-treatment) samples. In pre-treatment peripheral blood samples, TCR evenness (p=0.032) was associated with 1 year EFS. In FFPE post-treatment samples, 1 year EFS as well as MPR were significantly associated with increased TCR richness (p=0.0168 and 0.0134) and Shannon diversity (p=0.0278 and p=0.0334). Furthermore, nodal clearance was significantly associated with TCR richness and Shannon diversity in post-treatment tissue samples (p=0.0015, p=0.0087).

Conclusions: Our results show that TCR repertoire measured in peripheral blood samples and tumor tissue may provide a useful tool for predicting risk of recurrence after neoadjuvant sequential chemo- immunotherapy with durvalumab in patients with resectable stage IIIA(N2) NSCLC.


V84 Brigatinib (BRG) beim Crizotinib (CRZ)-refraktären ALK-positiven nicht-kleinzelligen Lungenkarzinom (NSCLC): Finale Ergebnisse der Phase 1/2- und der Phase 2 (ALTA)-Studie
Rudolf Maria Huber, München, D

Introduction: We report here long-term efficacy and safety from BRG Phase 1/2 and ALTA trials.

Methods: The Phase 1/2 study was a single-arm, open-label trial (NCT01449461) of BRG 30-300 mg/day in patients (pts) with advanced malignancies. ALTA (NCT02094573) randomized pts with CRZ- refractory ALK+ NSCLC to receive BRG at 90 mg qd (arm A) or 180 mg qd (7-day lead-in at 90 mg; arm B). For Phase 1/2, investigator (INV) assessments of confirmed ORR (cORR; RECIST v1.1), DoR, PFS, OS, and safety in pts with ALK+ NSCLC are reported. ALTA primary endpoint was cORR per INV; secondary endpoints included cORR (per IRC), DoR, PFS, and OS.

Results: In the Phase 1/2 study, 137 pts received BRG; of these, 79 pts had ALK+ NSCLC; 71/79 had prior CRZ. BRG doses received by these 79 pts: 60 mg qd, n=1; 90 mg qd, n=14; 120 mg/day, n=6; 180 mg qd [7-day lead-in at 90 mg], n=28; 180 mg/day, n=25; 240 mg/day or 300 mg qd, n=5). In ALTA, 222 pts with CRZ-refractory ALK+ NSCLC were randomized (n=112/110, arm A/B). At the end of the Phase 1/2 study (Feb 18, 2020), with median 27.7 mo follow-up (~67 mo after last pt enrolled), 10 pts remained on BRG. At the end of ALTA (Feb 27, 2020), with median 19.6/28.3 mo follow-up in arm A/B (~53 mo after last pt enrolled), 10/17 pts in A/B remained on treatment. Table shows efficacy from both studies. In ALTA, IRC-assessed intracranial cORR in pts with measurable baseline brain metastases was 50% (13/26) in arm A and 67% (12/18) in arm B; Kaplan-Meier (KM) estimated median intracranial DoR was 9.4 mo (95% CI, 3.7, not reached [NR]) in arm A and 16.6 mo (3.7, NR) in arm B. No new safety signals were identified with long-term follow-up. TEAEs led to dose interruption in (Phase 1/2/ALTA arm A/B) 59%49%/61%, dose reduction in 13%/8%/33%, and discontinuation in 10%/4%/13%.

Conclusions: BRG showed sustained long-term activity and manageable safety in CRZ-refractory ALK+ NSCLC. The 180-mg qd dose (7-day lead-in at 90 mg) led to numerically higher median PFS and OS. Final results are similar to those reported for other ALK TKIs in this setting.


V289 Wirksamkeit von Capmatinib bei NSCLC Patienten, die mittels NGS-basierter Flüssigbiopsietestung als METex14-mutiert identifiziert wurden: Ergebnisse aus der GEOMETRY mono-1 Studie
Jürgen Wolf, Köln, D

Capmatinib was approved for patients (pts) with advanced MET exon 14 skipping mutation (METex14) NSCLC in the US and Japan, with the FoundationOne® CDx (tissue NGS assay), based on results of the GEOMETRY mono-1 study. Here, we report efficacy findings in pts from GEOMETRY mono-1, who were identified as METex14 using a liquid biopsy NGS test (LDx), which detects METex14 in ctDNA.

During the GEOMETRY mono-1 study, pts were screened for METex14 status using a METex14 RT-PCR clinical trial assay (CTA) on FFPE tissue. Clinical validation of the LDx was performed using plasma samples from pts enrolled in the study, which include METex14-positive samples from Cohort (C)4 (pretreated) and C5b (treatment-naïve), in addition to METex14-negative samples from C1b, C2, and C3, and 21 tissue-matched NSCLC plasma samples from commercial sources to supplement the total number of METex14 deletion negative patients. Concordance of the CTA and LDx were evaluated by positive percent agreement (PPA) and negative percent agreement (NPA). This retrospective analysis reports ORR, DOR, and PFS, all by BIRC, and OS in pts identified as METex14 by the LDx (data cutoff: Sep 18, 2020).

Of the 97 pts with METex14 NSCLC in C4 (n=69) and C5b (n=28), 88 pts had plasma volume ≥2.5mL and cell free DNA ≥20ng (minimum input); of these 57 were LDx positive, 26 were negative; 5 had invalid sequencing results. Of the 97 CTA METex14-negative patients who met minimum input requirements, 88 were LDx negative and 9 had invalid sequencing results; none of the CTA MET ex14-negative pts (n=97) were reported as positive by the LDx. The PPA and NPA for these were 68.7% (95%CI: 57.6%, 78.4%) and 100% (95%CI: 95.9%, 100%), respectively, when excluding LDx invalid results. In pts identified as METex14 positive by LDx, the ORR (95%CI) was 81.3% (54.4‒96.0; n=16) in C5b and 48.8% (32.9‒64.9; n=41) in C4; median DOR (95%CI) was 20.3 (4.2, NE; n=13) months in C5b and 9.8 (4.2‒19.5; n=20) months in C4; median PFS (95%CI) was 12.4 (4.5‒NE; n=16) months in C5b and 5.4 (4.0‒6.6; n=41) months in C4; median OS was 17.9 (9.8‒NE; n=16) months in C5b and 13.6 (6.6‒23.3; n=41) months in C4.

Current findings from the GEOMETRY mono-1 study support the activity of capmatinib in advanced NSCLC pts with METex14 identified using LDx. For pts identified as METex14-negative by the LDx, further testing should be performed on tissue samples, as a negative LDx result does not preclude a positive result by tissue biopsy.