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Updates on Lung Cancer

IMpower133: characterisation of long-term survivors treated with first line chemotherapy ± atezolizumab in extensive-stage small cell lung cancer

In IMpower133, atezolizumab + CP/ET for first-line treatment of ES-SCLC led to improved OS and PFS vs placebo + CP/ET. Additional follow-up showed persistent OS benefit with the atezolizumab + CP/ET regimen.

However, there is limited data regarding the characteristics of patients with ES-SCLC who experience long-term survival with CIT and chemotherapy. At ESMO 2020, an exploratory analyses of IMpower133 to characterise long-term survivors (LTS) – defined as patients who lived ≥18 months since randomization, was presented.

In IMpower133, more LTS were treated with atezolizumab + CP/ET (33.5%) than with placebo + CP/ET (20.4%).

Among patient and disease subgroups, including those with advanced age and greater disease burden, more LTS received atezolizumab.

The authors concluded that the exploratory analyses suggest that patients with ES-SCLC can derive benefit from the addition of atezolizumab to chemotherapy. This clinical benefit was regardless of the patient and disease characteristics, thereby confirming atezolizumab + CP/ET as the standard of care for patients with untreated ES-SCLC.

Four-Year Survival in Randomised Phase II (POPLAR) and Phase III (OAK) Studies of Atezolizumab vs Docetaxel in Pre-treated NSCLC

The efficacy and safety of the anti–PD-L1 cancer immunotherapy atezolizumab in patients with previously treated advanced NSCLC was investigated initially in a Phase II study, POPLAR, and later via a confirmatory Phase III study, OAK.

Both studies have shown significant improvements in survival outcomes, with an acceptable benefit-risk profile, compared with docetaxel in an all-comer population.

Long-term follow-up of the randomised POPLAR and OAK studies through a 4-year period suggests a consistently greater survival benefit with atezolizumab vs docetaxel in previously treated patients with advanced NSCLC, irrespective of PD-L1 expression levels or histology.

The majority of docetaxel-arm 4-year survivors received anti–PD-L1/PD-1 antibody immunotherapy as a subsequent anti-cancer therapy.

Atezolizumab showed a consistent and manageable safety profile with no new Grade 4 or 5 AEs reported with longer follow-up in either study.

KEYNOTE-024 5-Year OS Update: First-Line Pembrolizumab vs Platinum-Based Chemotherapy in Patients with Metastatic Non–Small-Cell Lung Cancer and PD-L1 Tumor Proportion Score ≥50.

KEYNOTE-024 showed superiority of first-line pembrolizumab monotherapy versus platinum-based chemotherapy for metastatic NSCLC with PD-L1 TPS ≥50% and without sensitizing EGFR/ALK alterations at 11.2 months median follow-up. With 5 years follow-up, the efficacy and safety outcomes were reported at ESMO 2020.

For the ITT population, pembrolizumab continues to show meaningful improvements in OS and durable responses versus chemotherapy in KEYNOTE-024

Despite the 66% effective crossover rate, the 5-year OS rate was approximately doubled in the pembrolizumab group (31.9% vs 16.3%) with a median DOR of 29.1 months in the pembrolizumab group. Of note, patients who completed 35 cycles (2 years) of pembrolizumab experienced long-term OS.

Incidence of any-grade and grade 3−5 treatment-related AEs was lower with pembrolizumab versus chemotherapy. Long term treatment with pembrolizumab did not identify new safety signals.

Second-course pembrolizumab at the time of disease progression was feasible and associated with antitumor activity.

In conclusion, KEYNOTE-024 is the first phase 3 study to demonstrate 5-year efficacy for first-line immunotherapy and demonstrates that pembrolizumab monotherapy is an effective first-line treatment regimen in patients with metastatic NSCLC and PD-L1 TPS ≥50%.

Amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation EGFR tyrosine kinase inhibitor, in advanced EGFR-mutant NSCL

In preclinical studies, the combination of amivantamab (EGFR-MET bispecific antibody) with lazertinib demonstrates synergistic inhibition of tumor growth. At ESMO 2020, the safety and early efficacy results of patients receiving amivantamab in combination with lazertinib in the phase 1 CHRYSALIS study (NCT02609776) were presented.

Amivantamab can be safely combined with lazertinib. No dose-limiting toxicities identified during dose escalation. Combination dose tolerated, with low rates of treatment discontinuation (6%) and grade ≥3 TRAE (11%). 65% of patients experienced IRR, all grade 1 – 2, occurring with the first infusion.

Amivantamab with lazertinib is efficacious in advanced EGFRm NSCLC. 100% ORR in treatment-naïve cohort.

36% ORR in osimertinib-resistant, chemo-naïve cohort ̶ Analysis of efficacy by mechanism of resistance is ongoing

New studies with amivantamab + lazertinib combination started: Phase 3 MARIPOSAa study in frontline EGFRm NSCLC vs osimertinib as well as Phase 2 CHRYSALIS-2 study in osimertinib-resistant and chemotherapy-relapsed setting.

An international randomized trial comparing Postoperative Radiotherapy (PORT) to no PORT, in patients with completely resected NSCLC and mediastinal N2involvement

LungART is the first European randomized study evaluating modern PORT after complete resection, in patients selected predominantly with PET scan and having received (neo) adjuvant CT.

3-year DFS (43.8% in the control arm and 47.1% in the PORT arm) was higher than expected in both arms. Mediastinal relapse was reduced (46% in CA vs 25% in PORT). In addition, PORT was associated with a non-statistically significant 15% increase in DFS among stage IIIAN2 pts.

However, there were more toxicities observed in the PORT arm, especially cardiopulmonary that need to be further explored.  

As such, the authors noted that conformal PORT cannot be recommended as Standard of Care in all completely resected Stage IIIAN2 NSCLC patients. However, further analyses are being planned (QA surgery and PORT, Patterns of failure, TR etc.).

Lorlatinib vs Crizotinib in the First-line Treatment of Patients with Advanced ALK-Positive Non-Small Cell Lung Cancer: Results of the Phase 3 CROWN Study

The CROWN study is a randomised Phase 3 study comparing lorlatinib vs crizotinib as first-line treatment in ALK-positive NSCLC − results from a planned interim analysis are presented.

Lorlatinib resulted in a significantly longer PFS, significantly higher overall and IC response rates.

Lorlatinib IC response rate was 82% in patients with measurable brain metastases, with a complete response rate of 71% and significantly longer time to IC progression.

Global QoL scores was also improved compared to crizotinib.

The safety profile of lorlatinib was similar to that reported in previous studies. Grade 3/4 AEs were more frequent with lorlatinib than crizotinib, however the majority were laboratory abnormalities that were asymptomatic and readily managed.

As such, the authors concluded that these results support the use of lorlatinib as an effective first-line therapy for patients with advanced ALK+ NSCLC.

Osimertinib adjuvant therapy in patients with resected EGFR mutated NSCLC (ADAURA): CNS disease recurrence.

The phase 3, randomized ADAURA trial assessed the efficacy and safety of osimertinib as compared with placebo in patients with completely resected stage IB to IIIA.

In ADAURA, adjuvant osimertinib demonstrated a highly statistically significant and clinically meaningful improvement in DFS in patients with stage IBꟷIIIA EGFRm NSCLC.

Patients who received osimertinib had fewer local / regional and distant relapses than those who received placebo, with a lower incidence of metastatic disease in those patients with recurrence, including fewer CNS recurrence events.

Adjuvant osimertinib demonstrated a clinically meaningful improvement in CNS DFS compared with placebo. HR: 0.18 (95% CI: 0.10, 0.33; p<0.0001), equating to an 82% reduction in risk of CNS disease recurrence or death.

CNS disease recurrence was less likely with osimertinib compared with placebo, with a conditional probability of <1% at 18 months with osimertinib.

In conclusion, the authors noted that the reduced risk of local and distant recurrence and improved CNS DFS reinforce adjuvant osimertinib as a highly effective, practice changing treatment for patients with stage IB / II / IIIA EGFRm NSCLC following complete tumour resection.

Durability of clinical benefit and biomarkers in patients with advanced non-small cell lung cancer (NSCLC) treated with AMG 510 (sotorasib): CodeBreaK 100

Sotorasib (previously known as AMG 510) is a novel, highly-selective, first-in-class, oral KRASG12C inhibitor. CodeBreaK 100 was a phase I, multicenter, dose escalation/expansion study that included adult patients with KRAS p.G12C mutant solid tumors. The primary endpoint was safety, and key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS). The authors also evaluated KRAS p.G12C mutant allele frequency (MAF) and programmed cell death-ligand 1 (PD-L1) level. The trial enrolled 129 patients across 13 different tumor types, including 59 patients with NSCLC which was presented at ESMO 2020

Sotorasib showed a favorable safety profile, with no dose-limiting toxicities or treatment-related fatal AEs. Grade 3 or 4 treatment-related AEs occurred in 18.6% of patients.

In terms of clinical benefit, sotorasib demonstrated durable disease control in heavily pre-treated patients with NSCLC, with a confirmed ORR of 32.2% for all patients and 35.3% for the 960 mg cohort. DCR was 88.1% for all patients and 91.2% for the 960 mg cohort. Median PFS was 6.3 months in all patients, with median duration of response of 10.9 months.

In addition, sotorasib demonstrated clinical activity in NSCLC across a range of KRAS p.G12C MAFs, PD-L1 expression levels, TMB plasma levels, and co-mutational profiles.

The authors concluded that the novel, first-in-class KRAS p.G12C inhibitor sotorasib has a good safety profile and appears to have activity in non-small cell lung cancer (NSCLC). Additional CodeBreaK trials evaluating sotorasib as monotherapy or in combination with other anticancer agents are currently underway (CodeBreaK 100, CodeBreaK 200, CodeBreaK 101, CodeBreaK 105).

IMpower150: Updated Efficacy Analysis in Patients With EGFR Mutations

Previously published results from the Phase III IMpower150 study (data cutoff: 22 January 2018) showed prolonged PFS and OS with the combination of atezolizumab plus BCP treatment (ABCP) compared with BCP in patients with first-line non-squamous advanced NSCLC, including patients with EGFR genomic alterations.

With ≈ 20 months of additional follow-up beyond that of prior analyses, the long-term efficacy of atezolizumab and/or bevacizumab with chemotherapy in subpopulations of patients with EGFR mutations in IMpower150 was presented at ESMO 2020.

With the longer follow-up, OS continued to be observed in the ABCP vs BCP arm in those with sensitising mutations including those who received prior TKI therapy.

Increased ORR and longer DOR were also seen with ABCP vs BCP. However, there were no clinical benefit seen with ACP vs BCP across EGFR mutation subgroups.

As such, the authors concluded that the ABCP regimen may represent a new treatment option for patients with sensitising EGFR mutations in whom TKIs have failed.

Editor: Tan Wan Ling

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