The introduction of targeted treatments and more recently immune checkpoint inhibitors (ICI) to the treatment of metastatic non-small cell lung cancer (NSCLC) has dramatically changed the prognosis of selected patients. For patients with oncogene-addicted metastatic NSCLC harbouring an epidermal growth factor receptor (EGFR) or v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) mutation or an anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) gene alteration (translocation, fusion, amplification) mutation-specific tyrosine kinase inhibitors (TKI) are already first-line standard treatment, while targeted treatment for other driver mutations affecting MET, RET, human epidermal growth factor receptor (HER) 2, tropomyosin receptor kinases (TRK) 1–3 and others are currently under investigation. The role of ICI in these patient subgroups is currently under debate. This article summarises a round-table discussion organised by ESMO Open in Vienna in July 2018. It reviews current clinical data on ICI treatment in patients with metastatic oncogene-addicted NSCLC and discusses molecular diagnostic assessment, potential biomarkers and radiological methods for response evaluation of ICI treatment. The round-table panel concluded ICI should only be considered in patients with oncogene-addicted NSCLC after exhaustion of effective targeted therapies and in some cases possibly after all other therapies including chemotherapies. More clinical trials on combination therapies and biomarkers for ICI therapy based on the specific differing characteristics of oncogene-addicted NSCLC need to be conducted.

IntroductionIncreasingly more adolescent and young adult (AYA, aged 18–39 years) patients with an uncertain and/or poor cancer prognosis (UPCP) are gaining life-years because of novel treatments or refinement of established therapies, and sometimes even face the prospect of long-term disease control. This study aims to examine the challenges of AYAs with a UPCP in daily life to inform the development of AYA care programs.MethodsSemi-structured in-depth interviews were conducted among AYAs with a UPCP. Since we expected differences in experiences between three AYA subgroups, we interviewed patients of these subgroups (1): traditional survivors (2), low-grade glioma survivors, and (3) new survivors. Interviews were analyzed using elements of grounded theory. AYA patients were actively involved as research partners.ResultsIn total 46 AYAs with UPCP participated and shared their challenges in daily life. They were on average 33.4 years old (age range 23–44) and most of them were women (63%). The most common tumor types were low-grade gliomas (16), sarcomas (7), breast cancers (6), and lung cancers (6). We identified five primary themes: (1) feeling inferior to previous self and others (e.g. feeling useless, who wants me in a relationship), (2) feeling of being alone (e.g. lonely thoughts, nobody really gets me), (3) ongoing confrontation (e.g. it is always there, own decline), (4) grief about life (e.g. grief about life I did not get, grief about old life), and (5) loss of control over the future (e.g. not able to make future plans, waiting for growth). Although all of the challenges were identified in the three AYA subgroups, the perceived intensity of the challenges differed slightly between the subgroups.DiscussionAYAs living with a UPCP experience challenges associated to their sense of altered identity, their position in the social network, and the future uncertainties. This study highlights the importance to recognize and acknowledge the unique challenges of this group. To provide age-specific care, it is important to embed acceptance and commitment therapy and AYA peer support within the healthcare system and other care programs to support AYAs to live well with their disease.

TPS9159 Background: RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1–2% of non-small cell lung cancer (NSCLC). Pralsetinib is a potent, selective RET inhibitor, approved in the US and EU for the treatment of metastatic RET fusion–positive NSCLC based on the phase 1/2 ARROW study (NCT03037385). In the ARROW study (data cutoff: Nov 6, 2020), patients who initiated 400 mg once daily (QD) of pralsetinib after platinum-based chemotherapy achieved an overall response rate (ORR) of 62%, per independent central review. In the treatment-naïve group, the ORR was 79%. Most treatment-related adverse events were grade 1–2 across the entire safety population treated at 400 mg QD (n=471). AcceleRET Lung, an international, open-label, randomized, phase 3 study (NCT04222972), will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) for first-line treatment of advanced/metastatic RET fusion–positive NSCLC. Abstracts for this study were previously submitted to the European Lung Cancer Congress 2020, the American Society of Clinical Oncology 2020 annual meeting, and 2020 World Conference on Lung Cancer. Methods: Approximately 226 patients with metastatic RET fusion–positive NSCLC will be randomized 1:1 to oral pralsetinib (400 mg QD) or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab [at investigator’s discretion]; squamous histology: platinum/gemcitabine or platinum + pembrolizumab + paclitaxel/nab-paclitaxel followed by maintenance pembrolizumab). Stratification factors include intended use of pembrolizumab, history of brain metastases, and Eastern Cooperative Oncology Group Performance Status. Key eligibility criteria include no prior systemic treatment for advanced/metastatic NSCLC; RET fusion–positive tumor by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients with central nervous system metastases were permitted if asymptomatic and on a stable dose of corticosteroids. Cross-over to receive pralsetinib upon disease progression will be permitted for patients randomized to SOC. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability and quality of life evaluations. Identification of potential biomarkers of antineoplastic activity and resistance was an exploratory endpoint. Recruitment has begun with sites (active or planned) in North America, Central America, Europe and Asia. Clinical trial information: NCT04222972.

TPS9142 Background: Although 3rd-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, are highly effective in front-line metastatic EGFR-mutated ( EGFRm) NSCLC, treatment resistance ultimately occurs, including the emergence of the on-target C797X mutation for which there are no approved TKIs. BLU-701 is an investigational, reversible, brain-penetrant, wildtype-sparing oral TKI with nanomolar potency on common activating (exon 19 deletion and L858R) and C797X resistance mutations (Tavera L et al. AACR 2022). BLU-701 has shown promising preclinical data, including antitumor central nervous system (CNS) activity that may improve patient outcomes. Additionally, combining BLU-701 with standard of care therapies may provide enhanced disease control across multiple lines of treatment, including against heterogenous tumors, in patients with EGFRm NSCLC. Methods: HARMONY (NCT05153408) is an ongoing, global phase 1/2, open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of BLU-701 as a monotherapy or in combination with osimertinib or platinum-based chemotherapy in patients with EGFRm NSCLC. Key inclusion criteria include patients ≥18 years of age with metastatic EGFRm NSCLC; Eastern Cooperative Oncology Group performance status 0–1; and previous treatment with ≥1 EGFR-targeted TKI. Patients in the phase 2 monotherapy part must harbor an EGFR C797X resistance mutation (locally assessed). Key exclusion criteria are tumors harboring EGFR T790M mutations, EGFR exon 20 insertions, or other known driver alterations, including KRAS, BRAF V600E, NTRK1/2/3, HER2, ALK, ROS1, MET, or RET. Phase 1 primary endpoints are maximum tolerated dose, recommended phase 2 dose (RP2D), and safety. The phase 2 primary endpoint is overall response rate (ORR) by RECIST 1.1. Secondary endpoints include ORR (phase 1), duration of response, and PK/PD (phase 1 and phase 2); disease control rate, progression-free survival, overall survival, antitumor CNS activity, and safety (phase 2). The phase 1 dose escalation will adopt a Bayesian optimal interval design. Patients will be enrolled into 3 treatment cohorts: part 1A (n≈40–80; BLU-701), part 1B (n≈35; BLU-701 + osimertinib), and part 1C (n≈18; BLU-701 + carboplatin and pemetrexed). Patients in the phase 2 dose expansion (n≈24) will be treated at the RP2D of BLU-701 as monotherapy. Patients may receive treatment until disease progression, unacceptable toxicity, or other discontinuation criteria are met. Enrollment in this study has started, and sites will be open across North America, Europe, and Asia. Clinical trial information: NCT05153408.

9011 Background: Despite improved frontline OSI treatment outcomes, patients (pts) with advanced EGFRm NSCLC inevitably progress, with worse outcomes in the EGFR L858R subgroup (median PFS of 14.4 vs 21.4 mo in pts with exon 19 deletions). BLU-945 is an investigational, next-generation, oral tyrosine kinase inhibitor (TKI) that targets common EGFR-activating and T790M and C797X resistance mutations, while being selective against EGFR wild type (WT). Preclinically, BLU-945 in combination (combo) with OSI had enhanced potency on L858R and extended antitumor response durability versus OSI alone. SYMPHONY (NCT04862780) is an ongoing first-in-human phase 1/2 study of BLU-945 monotherapy (mono) or combo with OSI. Methods: In the phase 1 dose escalation, pts (aged ≥18 y; metastatic EGFRm NSCLC; ECOG PS 0–1; treated with ≥1 EGFR TKI) received BLU-945 mono starting at 25 mg QD. Pts progressing on OSI could receive BLU-945 with 80 mg OSI starting at 50% of the highest safe BLU-945 mono dose. Each dose escalation followed a Bayesian Optimal Interval design. Safety, including dose-limiting toxicities (DLT), PK, and circulating tumor DNA (ctDNA) mutational status were assessed. Results: As of Jan 6, 2023, 108 pts received BLU-945 mono (25–600 mg QD; 100–300 mg BID). Pts had a median of 3 lines of prior therapy and were genomically complex with ctDNA detectable EGFR on-target and/or off-target resistance alterations (46%) at baseline. DLTs included alanine transaminase (ALT) and aspartate transaminase (AST) elevation, hepatic cytolysis, fatigue, nausea, vomiting, and hyponatremia, occurring at doses of ≥400 mg/d. The maximum tolerated dose was 500 mg/d. The most common AEs were nausea (42%), headache (40%), increased ALT (38%), increased AST (37%), and vomiting (32%). Robust on-target EGFR activity was observed with ctDNA reduction on day 15 in 90%, 85% and 70% of EGFR T790M, C797S, and L858R alleles at ≥400 mg/d doses, respectively. At ≥400 mg/d, 48% had tumor shrinkage, including partial responses (PRs). Twenty-five pts received BLU-945 (200–400 mg QD; 100–200 mg BID) combo with OSI. Pts had a median of 2 lines of prior therapy. The most common combo AEs were fatigue (36%), diarrhea (32%), headache (32%), and nausea (28%). Other EGFR WT AEs were dry skin (20%) and rash (8%). One DLT (Grade 4 pneumonitis) was reported in the BLU-945 300 mg QD with OSI group. Tumor reductions, including PRs in 2 pts progressing on OSI, were observed at ≥300 mg/d. Dose escalation is ongoing. Conclusions: BLU-945 mono and combo with OSI were generally well tolerated and showed robust on-target EGFR ctDNA reduction, with tumor shrinkage in genomically heterogeneous, heavily pretreated pts. Combo showed responses at BLU-945 doses lower than in mono, consistent with additive benefit. The combo safety profile and on-target activity provide rationale for further development in front line. Clinical trial information: NCT04862780 .