Background

APPLE is a 3 arms phase II non-comparative trial exploring the sequential treatment approach of gefitinib followed by osimertinib or osimertinib frontline in patients with advanced EGFR-mutant NSCLC. Here we report the exploratory analysis of the outcome with osimertinib frontline compared to a sequential approach.

Methods

Patients were randomized to: arm A (osimertinib until RECIST progression -PD-), arm B (gefitinib until the emergence of circulating tumor DNA EGFR T790M mutation or RECIST PD) or arm C (gefitinib until RECIST PD), and then switch to osimertinib in both arms B and C. In this analysis, arms B and C were pooled. Primary endpoint: Progression Free Survival rate “on osimertinib” at 18 months (PFSR-OSI-18) in arm B (H₀: PFSR-OSI-18 of ≤40%). Secondary endpoints: overall survival (OS) and Brain PFS (BPFS). Primary analyses were performed in per-protocol population (PPP). In all arms, contrast-enhanced brain CT-scan was performed every 8 weeks.

Results

From 11/2017 to 02/2020, 156 patients were randomized (arm A:53, arm B/ C:103), and 136 were included in the PPP. Most patients were females (56.6% and 69.9%), with EGFR Del19 (66% and 64%). Baseline brain metastases: 19% and 29.1%, respectively. In pooled arms B/C, 70% of patients received osimertinib at PD. In arm A, PFS on osimertinib was 19.5 months. The PFSR-OSI-18 was 51.1% in Arm A and 61% in pooled arms B/C. The median OS was NR in arm A vs 42.8 (95% CI: 28.6-NR) months (mo) in pooled arm B/C, with 18-months OS of 84.4% and 82.3%, respectively. In all arms, 68 brain progression events were observed. Median time to brain PD in arm A and B/C were 34.3 mo (95% confidence interval, CI:26.9-NR) and 22.3 mo (95%CI:18.6-22.3), and corresponding hazard ratio was 0.54 (90% CI: 0.34-0.86) with 18-months BPFS of 82.2% and 63.5%, respectively.

Conclusions

In advanced EGFR mutant-NSCLC, upfront treatment with osimertinib shows a significant reduction in the risk of brain progression, with comparable OS versus the sequential treatment approach.

Clinical trial identification

NCT02856893

Background

Most patients with EGFR mutant NSCLC who have an initial response to OSI exhibit persistent residual disease that may enable emergence of acquired resistance. Eliminating residual disease with LCT may delay resistance and improve clinical outcomes. Safety of OSI with LCT, however, is not well defined. Here we report safety data from a multicenter randomized phase II study of OSI with or without LCT for patients with EGFR mutant NSCLC.

Methods

Metastatic NSCLC patients with tyrosine kinase inhibitor naïve EGFR mutation (L858R/Exon 19 deletion) or T790M resistance mutation after prior therapy received 6-12 weeks of induction OSI. Patients without progression per RECIST 1.1 were randomized to OSI alone vs LCT plus OSI until progression. Primary objective was progression free survival. Secondary objective was safety. Patients were evaluated every 8 weeks using CTCAE v4.0. All possible, probable, and definite treatment related AEs were analyzed. (ClinicalTrials.gov ID NCT03410043)

Results

From 2018 to 2022, 122 patients (median age: 65, range: 30-88) were randomized (63 to OSI alone; 59 to OSI plus LCT). Among 59 patients who received LCT, 35 (59%) received RT alone, 17 (29%) received surgery alone, and 7 (12%) received both RT and surgery. At median follow up of 16 months (range: 2-49), there were no grade 4/5 AEs. There was no significant difference in grade 3 AEs between OSI alone and OSI plus LCT (16% vs 29%; p = 0.08). The most common grade 3 AEs with OSI alone were hyponatremia (4.8%), transaminitis (4.8%), and pneumonitis (3.4%). The most common grade 3 AEs with OSI plus LCT were hyponatremia (6.8%), diarrhea (3.4%), empyema (3.4%), and pneumonitis (1.7%). Among 42 patients that received RT, 1 (2%) had a grade 3 AE possibly related to RT (non-cardiac chest pain). Among 24 surgical patients, 3 (13%) had surgery related grade 3 AEs (1 arterial injury, 2 empyema). Common grade 1-2 AEs with OSI plus LCT were fatigue (56%), diarrhea (45%), dyspnea (31%), cough (29%), pneumonitis (10%), dysphagia (12%), and esophagitis (7%).

Conclusions

OSI plus LCT is well tolerated in EGFR mutated metastatic NSCLC patients without significant increase in serious AEs compared to OSI alone.

Clinical trial identification

ClinicalTrials.gov ID NCT03410043

Background

Amivantamab (ami), an EGFR and MET bispecific antibody with immune cell-directing activity, is approved to treat patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations (Ex20ins) who progressed on prior platinum-based chemotherapy. This report presents long-term results for this population.

Methods

Pts with EGFR Ex20ins advanced NSCLC whose disease progressed on platinum-based chemotherapy were recruited in CHRYSALIS (NCT02609776). Pts who received the approved phase 2 dose of 1050 mg (1400 mg, ≥80 kg) by 08 Jun 2020 were included. Response was assessed by investigator per RECIST v1.1.

Results

As of Sep 2022, among 114 pts included, the median follow-up was 19.2 months and 48 (42%) pts alive. Investigator-assessed overall response rate (ORR) was 37% (95% CI, 28–46), with median duration of response of 12.5 months (95% CI, 6.9–19.3), median progression-free survival of 6.9 months (95% CI, 5.6–8.8), and median overall survival of 23 months (95% CI, 18.5–29.5). Activity was observed across subgroups, including the elderly (ORR of 32% and 33% for age ≥65 and ≥75, respectively), heavily pretreated pts (ORR of 53% for >2 prior lines, 42% for prior immunotherapy, and 52% for prior EGFR TKI therapy), or those sensitive or resistant to prior platinum-based chemotherapy (ORR of 36% and 31%, respectively). No new safety signals were detected, with rash (all grades, 89%) and infusion-related reactions (67%) remaining the most frequent toxicities.

There are 48 (42%) pts on ami for ≥12 (28-day) cycles. Treatment is ongoing in 15 (13%) pts (11 responders and 4 with stable disease as best response) who have received ami for a median of 2.6 years. An analysis comparing pts without and with sustained clinical benefit (≥12 cycles on ami) will presented at the meeting, including plasma ctDNA data.

Conclusions

Ami demonstrated robust efficacy that was consistently observed across post-platinum patients with EGFR Ex20ins NSCLC, including the elderly, those with multiple prior lines, or those who were platinum sensitive or refractory. A subgroup derived long-term benefit; the mechanisms for which will be explored further.

Clinical trial identification

NCT02609776

Editorial acknowledgement

Medical writing support was provided by Lumanity Communications, Inc

Background

In the CodeBreaK 200 phase 3 trial, sotorasib significantly improved PFS (primary endpoint) versus docetaxel in previously treated KRAS^G12C-mutated NSCLC. Previously described patient-reported outcomes (PROs) favored sotorasib over docetaxel for global health status, physical functioning, dyspnea, and cough (ESMO 2022, LBA10). Here, we report the severity and impact of symptoms on patients’ quality of life (QOL) in response to treatment.

Methods

In this trial, 345 patients who progressed after receiving platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to receive sotorasib (960 mg orally QD) or docetaxel (75 mg/m² intravenously Q3W). Well-established, validated questionnaires captured patients’ perception of their QOL and symptom burden: EuroQOL-5 Dimension Visual Analogue Scale (EQ-5D VAS), PRO-Common Terminology Criteria for Adverse Events (CTCAE), Brief Pain Inventory (BPI), and question GP5 from the Functional Assessment of Cancer Therapy Tool General form (FACT-G). For ordinal outcomes, change from baseline to week 12 was assessed with generalized estimating equations.

Results

Compared with patients receiving sotorasib, those receiving docetaxel were more severely bothered by their side effects (odds ratio [OR] 5.71) and experienced symptoms at a higher severity (pain: OR 2.94, aching muscles: OR 4.40, aching joints: OR 4.17, mouth or throat sores: OR 4.26). Further their symptoms more strongly interfered with their usual/daily activities (pain: OR 3.18, aching muscles: OR 3.90, aching joints: OR 10.68). QOL worsened five days after initial docetaxel treatment while remaining stable with sotorasib (change from baseline in VAS score: –8.4 vs 1.5). The VAS showed a long-term worsening of QOL with docetaxel while the VAS remained stable with sotorasib (–5.8 vs 2.2 at week 12).

Conclusions

Patients treated with sotorasib reported less severe symptoms than those treated with docetaxel; hence, their daily lives were positively affected. In addition to improving clinical efficacy outcomes, sotorasib maintained QOL versus docetaxel suggesting that sotorasib may be a more tolerable treatment option for patients with pretreated, KRAS^G12C-mutated advanced NSCLC.

Clinical trial identification

NCT04303780

Editorial acknowledgement

Medical writing support provided by Dr. Kristina Y. Aguilera (Ph.D.), Amgen Inc.