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ZENITH20 EVOKE-02 IMbrella A

Poziotinib Demonstrates Efficacy As A Third-Line Therapy For HER20 Exon 20 Mutation NSCLC

 

The development of tyrosine kinase inhibitors (TKIs) has represented a significant breakthrough in targeted therapies for non-small cell lung cancer (NSCLC). TKIs have increased the survival of patients with epidermal growth factor receptor (EGFR) mutant-positive NSCLC.1 In 2003, gefitinib was the first TKI to be approved by the USA Food and Drug Administration (FDA) for advanced stage NSCLC,2 followed by afatinib, osimertinib and erlotinib.

Poziotinib, a potent irreversible pan-HER TKI targeting exon 20 insertion mutations in EGFR and human epidermal growth factor receptor 2 (HER2), has yet to be approved by the FDA. Nevertheless, poziotinib shows promise in addressing unmet needs as a third-line therapy for

 

patients with EGFR and HER2 exon 20 mutations in NSCLC.3 The open-label Phase II ZENITH20 study (NCT03318939) indicated poziotinib has efficacy in patients with HER2 exon insertion NSCLC who had received at least two treatments previously and progressed.4

69 patients, who had previously received platinum-based therapies, were enrolled to receive 16mg of poziotinib once daily. Primary endpoints were duration of response (DOR), progression-free survival (PFS), and objective response rate (ORR). Additional previous treatments included immunotherapy (78%), HER2 antibody or antibody-drug conjugate (ADC) therapy (36%), TKIs (17%) and systemic therapy (16%).

The ORR of 30% exceeded the clinically meaningful threshold for the study, and the median PFS and DOR were 5.6 and 5.5 months respectively. The efficacy of poziotinib was determined to be consistent independent of the type and sequence of prior treatments. No new safety signals were additionally detected. Common adverse events (AEs) included rashes (46%), diarrhoea (28%) and mucositis (23%). 13% of patients discontinued the trial due to drug-related AEs, whilst 83% had dose interruptions and 72% had dose reductions.

Poziotinib has demonstrated clinically meaningful efficacy in patients with HER2 exon 20 insertion NSCLC who had received and progressed on at least two lines of therapy. The outcomes of this Phase II study warrant further research on the efficacy of poziotinib for this patient population.

Sacituzumab govitecan + Pembrolizumab Shows Efficacy In Untreated Metastatic NSCLC

 

Immunotherapies are crucial in increasing remission and survival in lung cancer. Immune checkpoint inhibitors (ICI) have significant benefits for survival in patients with NSCLC, whilst antibody-drug conjugates (ADCs) have been effective in minimising systemic effects despite powerful anticancer activity.5,6 Six ADCs have been approved by the FDA for solid tumours,7 with trastuzumab deruxtecan being a major ADC for HER2-mutant NSCLC. Nivolumab was the first FDA-approved ICI for lung cancer; other ICIs such as atezolizumab and durvalumab are being increasingly studied.8

Sacituzumab govitecan (SG), an ADC comprised of a topoisomerase inhibitor (govitecan) and an antibody against tumour-associated calcium signal transducer 2 (TACSTD2), has demonstrated durable responses and tolerability in advanced NSCLC.9 Pembrolizumab is an ICI targeting programmed death-ligand 1 (PD-L1), and in January 2023, the therapy was approved by the FDA as an adjuvant treatment for NSCLC.10 Preliminary results from the ongoing open-label Phase II EVOKE-02 trial (NCT05186974) indicated SG and pembrolizumab to be  effective as a first-line therapy for untreated metastatic NSCLC (mNSCLC).11

Adults with untreated mNSCLC were enrolled in cohorts A (PD-L1 tumour proportion score [TPS] ≥ 50%) and B (TPS < 50%). For 21 days, patients received 10mg/kg of SG on days 1 and 8, and 200mg of pembrolizumab on day 1. Trial endpoints are the ORR, PFS, DOR, overall survival (OS), safety and disease control rate.

 

44 patients (cohort A, n = 16; cohort B, n = 28) have enrolled in EVOKE-02. In efficacy-evaluable patients (cohort A, n = 8; cohort B, n = 18), ORR was 75% and 44% in cohorts A and B respectively. Treatment-emergent adverse events (TEAEs) were reported in 96% of safety-evaluable patients (n = 44). Common TEAEs included  diarrhoea (50%), anaemia (41%), asthenia (36%) and neutropenia (32%). Three TEAE-related deaths were reported, with 1 (2%) related to treatment. Overall, SG and pembrolizumab demonstrated encouraging early efficacy and a manageable safety profile in untreated mNSCLC. These preliminary results are consistent with the known safety of each agent.

Long-Term Follow-Up Analysis of Atezolizumab in ES-SCLC Demonstrates Durable 5-Year Survival Benefit

 

Atezolizumab is an ICI which targets PD-L1. The therapy was granted FDA approval in March 2019 for use in combination with chemotherapy as a first-line treatment for extensive stage small cell lung cancer (ES-SCLC),12 although it has also benefitted survival and quality of life in patients with NSCLC who are ineligible for platinum-based treatment.13 A long-term follow-up IMbrella A  extension study (NCT03148418) of the open-label Phase III IMpower133 trial (NCT02763579) indicated that atezolizumab and carboplatin/etoposide (A+CE) is able to provide

 

a durable survival benefit for up to 5 years in patients with ES-SCLC.14

Patients enrolled in the IMpower133 study were eligible for roll-over to the IMbrella A extension study if they continued atezolizumab at the end of the study or if they were in survival follow-up after discontinuing atezolizumab. The extension study assessed survival, treatment status and safety.

The median follow up was 59.4 months in the A+CE arm and 26.4 months in the placebo + CE arm (P+CE). 18 patients from the A+CE arm enrolled in IMbrella A. The 5-year OS of this arm was 12%, and of the 11 patients alive at the data cutoff date, the median age of the patients was 59 years old. Two of these patients had baseline brain metastases and none had baseline liver metastases. Seven patients had MD Anderson Cancer Centre SCLC subtype information based on neuroendocrine (SCLC-A and SCLC-N), non-neuroendocrine (SCLC-P) and immune-infiltrated (SCLC-I) transcriptional figures (SCLC-A, n = 1; SCLC-I, n = 2; SCLC-N, n = 4).

The results of demonstrate that durable survival benefit up to 5 years in possible with A+CE. This analysis is especially important as it is the first report of 5-year survival outcomes for patients who received first-line immunotherapy for ES-SCLC.

References

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  2. Kazandjian D, Blumenthal GM, Yuan W, et al. FDA approval of gefitinib for the treatment of patients with metastatic EGFR mutation-positive non-small cell lung cancer. Clin Cancer Res. 2016 Mar 15; 22(6):1307-1312.
  3. Elamin YY, Robichaux JP, Carter BW, et al. Poziotinib for EGFR exon 20 mutant NSCLC: clinical efficacy, resistance mechanisms and impact of insertion location on drug sensitivity. Cancer Cell. 2022 Jul 11; 40(7):754-767.
  4. Le X, Prelaj A, Bail C, et al. Efficacy and Safety of Poziotinib in HER2 Exon 20 Insertion NSCLC Patients who Received at Least 2 Previous Systemic Therapies Presented at WCLC 2023. September 9-12, 2023. Abstract MA13.09.
  5. Wang C, Li J, Zhang Q, et al. The landscape of immune checkpoint inhibitor therapy in advanced lung cancer. BMC Cancer. 2021 Aug 28; 21:968.
  6. Marei HE, Cenciarelli C, Hasan A. Potential of antibody-drug conjugates (ADCs) for cancer therapy. Cancer Cell International. 2022 Aug 13; 22(255).
  7. Martin J, Zacholski E, O’Cearbhaill R, et al. Controversial conversations in gynecologic cancer – the ABCs of ADCs (antibody drug conjugates). J Clin Med. 2023 Feb 2;45:101141
  8. Onoi K, Chihara Y, Uchino J, et al. Immune checkpoint inhibitors for lung cancer treatment: a review. J Clin Med. 2020 May; 9(5):1362.
  9. Heist RS, Guarino MJ , Masters G, et al. Therapy of advanced non-small cell lung cancer with an SN-38-anti-Trop-2 drug conjugate, Sacituzumab govitecan. J Clin Oncol. 2017 Aug 20; 35(24):2790-2797.
  10. The USA Food and Drug Administration. FDA approves pembrolizumab as adjuvant treatment for non-small cell lung cancer. 2023 [cited 2023 Sep 20]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-adjuvant-treatment-non-small-cell-lung-cancer
  11. Cho BC, Dols MC, Reyes Cabanillas R, et al. Sacituzumab Govitecan + Pembrolizumab in 1L Metastatic Non-Small Cell Lung Cancer: Preliminary Results of the EVOKE-02 Study Presented at WCLC 2023. September 9-12, 2023. Abstract OA05.04.
  12. Mathieu L, Shah S, Pai‐Scherf L, et al. FDA approval summary: atezolizumab and durvalumab in combination with platinum-based chemotherapy in extensive stage small cell lung cancer. Oncologist. 2021 May; 26(5):433-438.
  13. Lee SM, Schulz C, Prabhash K, et al. First-line atezolizumab monotherapy versus single-agent chemotherapy in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen (IPSOS): a phase 3, global, multicentre, open-label, randomised controlled study. The Lancet. 2023 Jul 6; 402(10400):451-463.
  14. Liu SV, Dziadziuszko R, Sugawara S, et al. Five-Year Survival in Patients with ES-SCLC Treated with Atezolizumab in IMpower133: Imbrella a Extension Study Results Presented at WCLC 2023. September 9-12, 2023. Abstract OA01.04.

Written by Vanessa Ankude

Edited by Simon Ng

The content of VJOncology is intended for healthcare professionals