Background

Patients (pts) with unresectable locally advanced non-small cell lung cancer (laNSCLC) who are not candidates for concurrent chemoradiation have often been excluded from immunotherapy trials, and their care represent an unmet medical need. We report post hoc analyses of pts with laNSCLC who received cemiplimab (anti–programmed cell death-1) from two Phase 3 clinical trials with long-term data.

Methods

EMPOWER-Lung 1 (NCT03088540) and EMPOWER-Lung 3 (NCT03409614) included pts with squamous or non-squamous NSCLC that was metastatic or locally advanced (not suitable for definitive concurrent chemoradiation) without EGFR, ALK or ROS1 genomic aberrations. In EMPOWER-Lung 1 pts were randomised 1:1 to first-line (1L) cemiplimab monotherapy or chemo for NSCLC with ≥50% programmed cell death-ligand 1 (PD-L1) expression. In EMPOWER-Lung 3 pts were randomised 2:1 to 1L cemiplimab + chemo or placebo + chemo regardless of PD-L1 expression level.

Results

In each trial, 15% of pts were treated for laNSCLC.

In EMPOWER-Lung 1, at ~3-year follow-up of pts with laNSCLC, 1L cemiplimab monotherapy led to a median overall survival (OS) of 26.1 vs 13.9 mo with chemo (HR: 0.67; 0.38–1.17; p=0.1532). Progression-free survival (PFS) was 8.1 vs 6.2 mo (HR: 0.56; 0.34–0.95; p=0.0286). Objective response rate (ORR) was 49% vs 31%. Median duration of response (DOR) was 18.8 vs 6.2 mo.

In EMPOWER-Lung 3, at ~2-year follow-up of pts with laNSCLC, greater efficacy was observed with 1L cemiplimab + chemo vs placebo + chemo. Median OS was 24.1 vs 13.8 mo (HR: 0.50; 0.27–0.95; p=0.0293) and median PFS was 12.5 vs 6.2 mo (HR: 0.34; 0.19–0.61; p=0.0002). ORR was 58% vs 29%. Median DOR was 27.8 vs 4.2 mo.

Conclusions

Long-term follow-up data from EMPOWER-Lung studies continue to suggest clinical benefit of 1L cemiplimab as monotherapy or in combination with platinum-based chemo in pts with unresectable laNSCLC who are not candidates for definitive concurrent chemoradiation.

Clinical trial identification

NCT03088540 and NCT03409614

Editorial acknowledgement

Medical writing support was provided by Rachel McGrandle MSc, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc., and Sanofi. Responsibility for all opinions, conclusions and data interpretation lies with the authors.

Background

In Phase 3 EMPOWER-Lung 1 study (NCT03088540), 1L CEMI monotherapy resulted in significantly longer OS and PFS versus chemotherapy (CHEMO) for pts with aNSCLC with no actionable genomic aberrations, whose tumours express PD-L1 ≥50%. The study included pts with treated, clinically stable, baseline brain metastases, a hard-to-treat and underrepresented population in clinical trials. We previously reported improved OS and PFS with 1L CEMI versus CHEMO for this subgroup. In this post hoc analysis, we report 3-year outcomes.

Methods

In EMPOWER-Lung 1, pts were randomised 1:1 to CEMI 350 mg IV Q3W or investigator’s choice of CHEMO. The overall median follow-up duration from randomization to data cut-off (4 March 2022) was 37.1 months (mo; range 24.0–56.5). Here, we analyzed pts with treated, clinically stable brain metastases (radiological stability not required).

Results

In all, 69/565 (12.2%) pts with PD-L1 ≥50% had treated, clinically stable brain metastases at randomization. Baseline characteristics in CEMI (n=34) vs CHEMO (n=35) groups were: median age, 60.0 (range: 45–76) vs 62.0 (range: 48–77) yrs; male, 97.1% vs 82.9%; and non-squamous histology, 85.3% vs 74.3%. CEMI showed superior efficacy outcomes vs CHEMO: longer median OS (not reached vs 20.7 mo; HR=0.42, 0.20-0.87), longer median PFS (12.5 vs 5.3 mo; HR=0.34, 0.18–0.63), a higher ORR (55.9% vs 11.4%) and a longer median duration of response (31.7 mo vs 12.5 mo; Table). After baseline, disease progression in brain occurred in 5 (14.7%) pts with CEMI vs 7 (20%) with CHEMO. Incidence of grade ≥3 TEAEs was 35.3% in the CEMI group vs 60.0% in CHEMO.

Conclusions

Three-year follow up data shows durable clinical benefits and an acceptable safety profile with 1L CEMI monotherapy in subgroup analysis of pts with aNSCLC and brain metastases. CEMI is generally well tolerated in this subgroup.

Clinical trial identification

NCT03088540

Editorial acknowledgement

This study was funded by Regeneron Pharmaceuticals, Inc. Medical writing and editorial support was provided by John Facciponte, PhD, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc., according to Good Publication Practice guidelines.

Background

Eftilagimod alpha (E), a soluble LAG-3 protein, acts as an MHC class II agonist triggering activation of antigen-presenting cells (APC) and CD8 T-cells. Stimulating APCs and subsequent T cell recruitment with efti may revert PD-1/PD-L1 resistance. We report updated results from Part B of the TACTI-002 trial: 2^nd line PD-1/PD-L1-resistant non-small cell lung carcinoma (NSCLC) patients (pts) treated with efti plus pembrolizumab (P).

Methods

Pts with metastatic NSCLC unselected for PD-L1 expression and with resistance to 1^st line PD-1/PD-L1 inhibitor-based therapy were enrolled. Primary endpoint (EP) was objective response rate (ORR) by iRECIST. Secondary EPs were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and tolerability. Post-hoc analysis included tumor growth kinetics (TGK). Pts received E (30 mg SC Q2W for eight 3-week cycles and then Q3W up to 1 yr) with P (200 mg IV Q3W up to 2 yrs). Imaging was performed every 9 wks and locally evaluated. PD-L1 TPS was assessed using IHC 22C3 kit.

Results

36 pts enrolled between Apr 2019 – Aug 2021. Median age was 67 yrs (46 – 84) and 61% were male. ECOG PS was 0 and 1 in 33% and 67% of pts. Pts had squamous (19%) and non-squamous (78%) histology. All PD-L1 subgroups were included: 39% with TPS <1% and 82% with TPS <50%. Pts received a PD-1/PD-L1 inhibitor alone (28%) or combined with platinum-based chemo (72%) as 1^st line therapy. Pts received median of 5 (2 – 35) P and 7 (2 – 22) E doses.

ORR and DCR (iRECIST) was 8.3% and 33%. All PRs were confirmed with pts on study 19+ m. TGK analysis was performed on pts with data available on the same lesions from prior failed therapy and post-baseline. Vast majority (83%) of pts showed deceleration (50%) in tumor growth or shrinkage (33%) of target lesions. Median PFS was 2.1 months with PFS rate at 6 m of 25%. 44% were alive at 12 m with median OS of 9.7 m. Most common (>15%) adverse events were decreased appetite (33%), dyspnea (31%), cough (28%), asthenia (22%), fatigue (19%), arthralgia (17%) and weight decreased (17%).

Conclusions

Efti + pembrolizumab is safe and shows encouraging signs of antitumor activity in NSCLC pts resistant to PD-1/PD-L1 inhibitors, warranting further investigation.

Clinical trial identification

2018-001994-25 (EudraCT)
NCT03625323 (ClinicalTrials.gov)

Background

In POSEIDON (NCT03164616), 1L T plus D and 4 cycles of platinum-based CT significantly improved PFS and OS vs CT in patients (pts) with EGFR/ALK wild-type mNSCLC leading to the approval of T+D+CT by the FDA; objective response rate (confirmed; 38.8% [95% CI, 33.6–44.3] and 41.5% [95% CI, 36.1–47.0] vs 24.4% [95% CI, 19.9–29.4]) and duration of response were also improved with both T+D+CT and D+CT vs CT. However, the relationship between number of CT cycles and patterns of response in pts with mNSCLC has not been fully established. Here we report outcomes in POSEIDON after 2 vs 4 CT cycles.

Methods

Pts (n=1013) were randomised (1:1:1) to 1L T+D+CT, D+CT or CT. Exploratory analyses of objective response (intent-to-treat [ITT] population and subgroups with mutations [m] in STK11, KEAP1 or KRAS) and safety (safety population) were conducted after 2 vs 4 CT cycles (week 6 vs 12 scans, respectively).

Results

78%, 82% and 74% of pts who received T+D+CT, D+CT or CT completed 4 CT cycles. 560 pts had stable disease (SD) after cycle (C) 2. Of these, 22.9% had partial response (PR) after C4 (Table). A similar trend was observed in pts with STK11m, KEAP1m or KRASm mNSCLC; in these pts, improvement appeared greatest with T+D+CT, although 95% CIs were wide and overlapping. Of 252 pts in the ITT with CR/PR after C2, 89.7% remained in response after C4 (Table). Reductions in median target lesion size occurred between C2 and C4 in all arms (data will be presented). The frequency of grade 3/4 adverse events (AEs) and serious AEs originating in C1–2 and C3–4 was similar (data will be presented).

Table 1

NSQ, non-squamous.

Conclusions

These exploratory data support the use of 4 CT cycles, when given with T (limited course) and D (until progression), to optimise response and tumour shrinkage in pts with mNSCLC, including some harder to treat subgroups. Two further CT cycles did not meaningfully add to toxicity or compromise the ability to administer planned CT.

Clinical trial identification

NCT03164616

Editorial acknowledgement

Medical writing support for the development of the abstract, under the direction of the authors, was provided by James Holland of Ashfield MedComms (Manchester, UK) an Inizio company, and funded by AstraZeneca.

Background

Pembrolizumab (pembro) ± chemotherapy is currently standard-of-care (SoC) first-line treatment for advanced/metastatic nonsquamous (NSQ) non-small cell lung cancer (NSCLC) without EGFR, BRAF or ALK/ROS aberrations. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression is often higher in cancerous vs healthy lung cells. Tusamitamab ravtansine (tusa rav) is a humanized CEACAM5-specific antibody-drug conjugate linked to DM4. Tusa rav monotherapy has shown encouraging antitumor activity and safety in patients with heavily pretreated CEACAM5-positive NSQ NSCLC.

Methods

CARMEN-LC05 assessed safety and antitumor activity of tusa rav in combination with SoC regimens: with pembro [T2]; with pembro + platinum-based chemotherapy (pCT) [T3]; and with pembro + pCT + pemetrexed [T4] in patients with advanced/metastatic NSQ NSCLC with CEACAM5 intensity of ≥2+ in ≥1% of tumor cells by immunohistochemistry. Tusa rav was given IV Q3W at 150 or 170 mg/m² in each treatment arm.

Results

As of Nov 28, 2022, 25 patients were treated for a median of 21 weeks (range 3–86); 12 (48%) were still on treatment. Dose-limiting toxicity of increased aspartate aminotransferase occurred in 1 patient in the T4 tusa rav 170 mg/m² group. The most frequent treatment-emergent adverse events (TEAE) were nausea (44%), diarrhea (36%), and asthenia (32%); Grade ≥3 events occurred in 68%; and Grade 5 events in 16% in the treatment period (all unrelated to tusa rav). Corneal TEAEs of any grade occurred in 24% of patients; but only 1 (keratitis) was Grade ≥3 in the T2 tusa rav 170 mg/m² group. Objective response rate (ORR) and disease control rate (DCR) for all patients were 40% and 88%, respectively.

Conclusions

Tusa rav combined with SoC showed encouraging antitumor activity across all treatment arms with a favorable safety profile, including in the T4 arm, and no new safety concerns, supporting ongoing evaluation of tusa rav.

Clinical trial identification

NCT04524689

Editorial acknowledgement

Medical writing assistance was provided by Julian Martins, MA, MBBS, and Michael Stillman, PhD, inScience Communications, Springer Healthcare (Paris, France and New York, NY, respectively) and was funded by Sanofi.

Background

Taletrectinib is a potent, next-generation, CNS-active, ROS1 tyrosine kinase inhibitor (TKI) with selectivity over TRKB. In previous reports from TRUST-I (NCT04395677), taletrectinib showed meaningful clinical efficacy and was well tolerated in pts with ROS1⁺ NSCLC (n=109) regardless of crizotinib (CRZ) pretreatment status. We report updated efficacy and safety data with ~1.5 yr follow-up.

Methods

TRUST-I is a multicenter, open-label, single-arm study with two cohorts: ROS1 TKI-naïve and CRZ-pretreated. Pts in both cohorts received taletrectinib 600 mg QD. Key study endpoints included IRC-confirmed ORR (cORR), DoR, disease control rate (DCR), PFS, and safety. A pooled analysis of ORR, PFS, and safety including pts from additional clinical trials was also conducted.

Results

In the 109 pts from TRUST-I (enrolled prior to Feb 2022) the median follow-up was 18.0 mo in TKI-naïve (n=67) and 16.9 mo in CRZ-pretreated pts (n=42). cORR was 92.5% in TKI-naïve and 52.6% in CRZ-pretreated pts (Table). Median DoR (mDoR) and mPFS were not reached. Intracranial-ORR was 91.6%; ORR in pts with G2032R was 80.0%. In a pooled analysis with phase 1 studies, ORR was 89.5% and 50.0% for TKI-naïve and CRZ-pretreated pts, respectively; mPFS was 33.2 mo and 9.8 mo. In 178 pts treated at 600 mg QD, treatment-emergent adverse events (TEAEs) were 92.7%; most (64.0%) were grade 1–2. The most common TEAEs were increased AST (60.7%), increased ALT (55.6%), and diarrhea (55.6%). Neurological TEAEs (dizziness, 18.5%; dysgeusia, 12.4%) and discontinuations due to TEAEs (3.4%) were low. Further updated results will be presented.

Table. Efficacy in pts treated with taletrectinib.

Conclusions

With additional follow-up, taletrectinib continued to demonstrate meaningful efficacy outcomes including high response rates, prolonged PFS, robust intracranial activity, activity against G2032R, and tolerable safety with low incidence of neurological AEs.

Clinical trial identification

NCT04395677

Editorial acknowledgement

Medical writing and editorial assistance were provided by Arpita Kulshrestha of Peloton Advantage, LLC, an OPEN Health company, and

funded by AnHeart Therapeutics, Inc.

Background

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various cancers, including lung cancer. Larotrectinib, a highly selective, central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor, demonstrated a 73% objective response rate (ORR) in 15 patients (pts) with TRK fusion lung cancer (Drilon et al. JCO Precis Oncol 2022). We report efficacy and safety with circulating tumour DNA (ctDNA) analysis in pts with TRK fusion lung cancer treated with larotrectinib.

Methods

Pts treated with larotrectinib in 2 clinical trials (NCT02122913, NCT02576431) were analysed. NTRK gene fusions were determined by local testing before enrolment. Larotrectinib was administered at 100 mg twice daily. Response was assessed by an independent review committee (IRC) per RECIST v1.1. ctDNA was analysed using Guardant360 and GuardantOMNI.

Results

As of 20 July 2021, 26 pts (12 pts with CNS metastases) were enrolled. Among 23 pts (10 pts with CNS metastases) evaluable per IRC, ORR was 83% (95% confidence interval [CI] 61–95; 2 complete response, 17 partial response, 4 stable disease). Median duration of response (DoR) was not reached (95% CI 9.5–not estimable [NE]), with a 12-month DoR rate of 72%. Median progression-free survival was not reached (95% CI 9.9–NE). Median overall survival was 40.7 months (95% CI 19.4–NE). Treatment-related adverse events were mostly Grade 1–2. ctDNA data were available for 14 pts. ctDNA analysis detected NTRK gene fusions in 6 of the 14 pts at treatment start. Assessment of baseline co-occurring mutations revealed the inclusion of 3 patients with mutation-positive NSCLC who had failed prior anti-EGFR therapy. By the data cut-off, 6 pts had progressed, with ctDNA data available for 5 pts. Potential acquired mutations were identified in 3 pts.

Conclusions

Larotrectinib demonstrated durable responses, extended survival benefit, and a favourable safety profile in patients with advanced lung cancer harbouring NTRK gene fusions, including those with treatment-naive NSCLC or with prior EGFR inhibitor therapy. ctDNA next-generation sequencing represents a promising technology to test NTRK gene fusions or resistance mutations.

Clinical trial identification

NCT02122913

NCT02576431

Editorial acknowledgement

Editorial acknowledgement: Editorial assistance was provided by Anastasija Pesevska, PharmD, and Joe Alling, BSc, (Scion, London UK) funded by Bayer HealthCare Pharmaceuticals, Inc.

Background

The ETOP-BOOSTER study explored the addition of bevacizumab to osimertinib as 2^nd line treatment in patients with pathologically confirmed advanced NSCLC harboring common sensitising EGFR (70% Exon 19 deletion; 30% Exon 21 L858R) and acquired EGFR T790M mutations (mt) and reported no difference in progression-free survival (PFS). An interaction of treatment outcomes by smoking status was previously identified. Pre-specified exploratory analysis of serial plasma samples using next generation sequencing (NGS) is reported.

Methods

Plasma circulating tumour DNA (ctDNA) analysis was conducted using Guardant360® on samples collected prospectively at baseline (BL), week 9 (w9) and at disease progression (PD). Multivariable Cox models, including interaction of treatment with smoking history, plasma EGFR T790M and TP53 mt at BL and longitudinally, and tumour EGFRmt status were analysed to assess their effect on outcome.

Results

From the 155 randomised patients, 136 (87%) had available blood samples at BL (68 in each arm), 110 (71%) at w9 and 65 (42%) at PD for plasma NGS analysis. EGFR T790M mt was detected in 71% (97/136) of BL samples and was not associated with PFS (Table).

At w9, EGFR T790M mt was undetected in 91% (of 80 available, initially mt, cases), while at PD it was present in 34% (of 47 cases available).

Smoking status was found to be predictive for PFS (interaction p=0.046), however it was not associated with TP53 mt, which was detected in 63% of BL samples. BL TP53 mt and tissue EGFR Exon 21 L858R were each found to be poor prognostic factors for PFS and overall survival independent of treatment.

D: Detected; ND: Not Detected; Int: Interaction; NR: Not Reached; NE: Not Estimable

Conclusions

The interaction of treatment with smoking, was confirmed for PFS in the current evaluation, and was not found to be driven by the presence of TP53 or EGFR T790M mt. BL TP53 mt and EGFR Exon 21 L858R were associated with poor outcome.

Clinical trial identification

EudraCT number: 2016-002029-12 / ETOP 10-16 BOOSTER