1 augustus 2022: Bron:  2022; 12: 902967. Published online 2022 Jun 8.

Hier een verslag van een case studie uit een fase II studie met totaal 603 deelnemende patienten waarvan bij 90 patiënten met uitgezaaide niet-kleincellige longkanker al een abstract beschikbaar is. In deze studie wordt onderzocht wat het effect is van de tyrosine kinase remmer Poziotinib. Deze patiënte bereikte in hele korte tijd (9 maanden) een complete remissie. Zelfs nadat ze drie maanden is gestopt wegens de bijwekringen. Een lagere dosering bij de hervatting zorgde al snel voor een gedeeltelijke remissie en in oktober 2021 werd een complete remissie gezien op de scans. Februari 2022 werd deze complete remissie bevestigd in nieuwe scan. 

Hier de vertaling van het abstract van de case studie omdat dit goed weergeeft hoe deze longkankerpatiënte extreem goed reageerde op dit medicijn. Abstract van de eerste 90 patiënten staat onderaan dit artikel. Veel patiënten bereikten een gedeeltelijke respons. 

Casusrapport: uitzonderlijke respons op poziotinib bij patiënt met gemetastaseerde niet-kleincellige longkanker met EGFR Exon 20-insertiemutatie

Van de verschillende tyrosinekinaseremmers (TKI's) van de volgende generatie die zijn getest tegen ongewone EFGR-veranderingen, is aangetoond dat poziotinib een krachtig middel is voor uitgezaaide niet-kleincellige longkanker (mNSCLC) met afwijkingen in HER2 exon 20, en goedkeuring door de FDA is gezocht in de eerder behandelde populatie. Poziotinib heeft ook activiteit aangetoond in mNSCLC met afwijkingen in EGFR-exon 20.

Hier rapporteren we het eerste gepubliceerde geval van een patiënt met mNSCLC met een EGFR-exon 20-insertiemutatie (EGFRex20ins) die een volledige respons (CR) bereikte onder behandeling met poziotinib als onderdeel van de ZENITH20-proef.
In januari 2021 werd bij een voormalige roker van 62-jarige vrouwelijke patiënt een recidief vastgesteld, na twee operaties en postoperatieve chemotherapie van mNSCLC, aan de lever en retroperitoneale knopen. Gezien de identificatie door Next Generation Sequencing (NGS) van de EGFRex20ins-mutatie, nam ze deel aan het ZENITH20-cohort 5-onderzoek, een multicenter fase 2-onderzoek gericht op het beoordelen van de werkzaamheid en veiligheid van poziotinib bij patiënten met EGFR- of HER2-exon 20-insertiemutaties.

Poziotinib als eerstelijns systemische therapie voor gemetastaseerde ziekte werd eind januari 2021 gestart en toegediend in de initiële dosering van 8 mg oraal tweemaal daags (BID). De meest voorkomende bijwerkingen vanaf het begin van de behandeling waren alopecia, maculaire huiduitslag, diarree, xerostomie en conjunctivitis. Vanwege deze bijwerkingen werd de behandeling met poziotinib gedurende de eerste 3 maanden stopgezet en in april 2021 verlaagd tot 6 mg oraal tweemaal daags.

Na de-escalatie van de dosis verbeterden de bijwerkingen en verdroeg de patiënt de behandeling beter zonder verdere onderbreking. Sinds de eerste herevaluatie (na 4 weken therapie) bleek de behandeling met poziotinib opmerkelijk effectief te zijn, met een partiële respons (PR) die vervolgens werd bevestigd in mei en juli 2021. Vervolgens bevestigde een CT-scan in oktober 2021 een CR, onderhouden met een goede tolerantie bij de laatste herevaluatie in februari 2022. De behandeling wordt nog steeds voortgezet met dezelfde dosering.

In dit geval was poziotinib een succesvol en goed verdragen eerstelijns behandelingsalternatief voor chemotherapie bij deze patiënt met EGFR-exon 20-insertie-gemuteerd mNSCLC.

Originele Engelstalige abstract: 

Abstract

Among the several next-generation tyrosine kinase inhibitors (TKIs) tested against uncommon EFGR alterations, poziotinib has been demonstrated to be a powerful agent for metastatic non-small-cell lung cancer (mNSCLC) with aberrations in HER2 exon 20, and FDA approval is being sought in the previously-treated population. Poziotinib has also shown activity in mNSCLC with aberrations in EGFR exon 20. Herein, we report the first published case of a patient affected by mNSCLC harbouring an EGFR exon 20 insertion (EGFRex20ins) mutation who achieved a complete response (CR) under treatment with poziotinib as part of the ZENITH20 trial. In January 2021, a former smoker 62-year-old female patient was diagnosed with relapse, after two surgeries and post-operative chemotherapy of mNSCLC, at liver and retroperitoneal nodes. Given the identification by Next Generation Sequencing (NGS) of EGFRex20ins mutation, she was enrolled in ZENITH20-cohort 5 trial, a phase 2 multicentre study aimed to assess the efficacy and safety of poziotinib in patients with EGFR or HER2 exon 20 insertion mutations. Poziotinib as first-line systemic therapy for metastatic disease was initiated at the end of January 2021 and administrated at the initial dosage of 8 mg orally twice daily (BID). The most common side effects from the beginning of the treatment included alopecia, macular skin rash, diarrhoea, xerostomia, and conjunctivitis. Due to these adverse events, poziotinib was discontinued during the first 3 months and then reduced to 6 mg orally BID in April 2021. After the dose de-escalation, the adverse events ameliorated, and the patient better tolerated the treatment without further interruption. Since the first reevaluation (after 4 weeks of therapy), the treatment with poziotinib resulted to be remarkably effective, with a partial response (PR) subsequently confirmed in May and July 2021. Then, in October 2021, a CT scan confirmed a CR, maintained with good tolerance at the last reevaluation in February 2022. Treatment is still ongoing at the same dosage. In this case, poziotinib has represented a successful and well-tolerated first-line treatment alternative to chemotherapy in this patient with EGFR exon 20 insertion mutated mNSCLC.


Poziotinib demonstrates antitumor activity in previously treated patients with HER2 exon 20 insertion NSCLC.

Clinical Trial
 
2022 Mar 1;40(7):710-718.
 doi: 10.1200/JCO.21.01323. Epub 2021 Nov 29.

Poziotinib in Non-Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial

Affiliations 

Abstract

Purpose: Insertion mutations in Erb-b2 receptor tyrosine kinase 2 gene (ERBB2 or HER2) exon 20 occur in 2%-5% of non-small-cell lung cancers (NSCLCs) and function as an oncogenic driver. Poziotinib, a tyrosine kinase inhibitor, was evaluated in previously treated patients with NSCLC with HER2 exon 20 insertions.

Methods: ZENITH20, a multicenter, multicohort, open-label phase II study, evaluated poziotinib in patients with advanced or metastatic NSCLC. In cohort 2, patients received poziotinib (16 mg) once daily. The primary end point was objective response rate evaluated by independent review committee (RECIST v1.1); secondary outcome measures were disease control rate, duration of response, progression-free survival, and safety and tolerability. Quality of life was assessed.

Results: Between October 2017 and March 2021, 90 patients with a median of two prior lines of therapy (range, 1-6) were treated. With a median follow-up of 9.0 months, objective response rate was 27.8% (95% CI, 18.9 to 38.2); 25 of 90 patients achieved a partial response. Disease control rate was 70.0% (95% CI, 59.4 to 79.2). Most patients (74%) had tumor reduction (median reduction 22%). Median progression-free survival was 5.5 months (95% CI, 3.9 to 5.8); median duration of response was 5.1 months (95% CI, 4.2 to 5.5). Clinical benefit was seen regardless of lines and types of prior therapy, presence of central nervous system metastasis, and types of HER2 mutations. Grade 3 or higher treatment-related adverse events included rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). Most patients had poziotinib dose reductions (76.7%), with median relative dose intensity of 71.5%. Permanent treatment discontinuation because of treatment-related adverse events occurred in 13.3% of patients.

Conclusion: Poziotinib demonstrates antitumor activity in previously treated patients with HER2 exon 20 insertion NSCLC.

Trial registration: ClinicalTrials.gov NCT03318939.

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