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10 mei 2020: Aanvullend op onderstaande studie blijkt dat Afatinib ook effectief kan zijn bij niet-kleincellige longkanker met andere mutaties en samengestelde mutaties dan de bekende EGFR-mutaties waarvoor Afatinib uitstekend werkzaam is. Afatinib heeft ook een brede activiteit tegen andere ongebruikelijke EGFR-mutaties en sommige exon 20-inserties. Bewijst deze studie: Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases die gratis is in te zien.

De verschillende voorkomende mutaties en beschikbare baselinekenmerken worden getoond in Table 2. 

Over het geheel genomen had:

  • 29% van de patiënten die in de analyse waren opgenomen een tumor met een belangrijke soms voorkomende mutatie (G719X, L861Q, S768I),
  • 25% had een T790M-mutatie (voornamelijk in de EGFR TKI –Voorbehandelde patiënten),
  • 21% had een insertie van exon 20,
  • 13% had andere soms voorkomende EGFR-mutaties 
  • 12% had een samengestelde mutatie.

De resultaten van afatinib bij de verschillende mutaties staat vermeld in (Table 3).

Abstract staat onderaan artikel.

Zie ook dit artikel: 

giotrifafatinib-gevolgd-door-osimertinib-laat-mediane-algehele-overleving-zien-van-bijna-vier-jaar-bij-patienten-met-egfr-t790m-positieve-niet-kleincellige-longkanker-nsclc-en-del19-mutatie.html

13 februari 2019: Aanvullend op onderstaande informatie (scroll verder naar onderen) een nieuwe recente studiepublicatie over effect van afatinib bij longkanker met HER2 mutaties pos.: 

Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study.

Met deze resultaten, waarbij opvalt dat maar weinig longkankerpatiënten een Her2 positieve mutatie hebben (1 procent ) maar als ze die hebben kan afatinib dus blijkbaar wel goed werken. Want van de 23 patienten bereikten er alsnog drie (13 procent) een gedeeltelijke respons van dus minimaal 50 procent vermindering van tumoromvang en aantal en meer dan de helft 13 patienten (57 procent) bereikten minimaal stabiele ziekte. En de mediane overall overleving steeg naar 23 maanden wat voor deze groep van patienten echt lang is. 

Hier het abstract van de studie. Zie ook verderop in dit artikel meer over effect van afatinib bij longkanker in het algemeen dus zonder gekoppeld te zijn aan een bepaalde mutatie.

Introduction

HER2 mutations occur in 1–3% of lung adenocarcinomas. With increasing use of next-generation sequencing at diagnosis, more patients with HER2-mutant tumours present for treatment. Few data are available to describe the clinical course and outcomes of these patients when treated with afatinib, a pan-HER inhibitor.

Methods

We identified patients with metastatic or recurrent HER2-mutant lung adenocarcinomas treated with afatinib among seven institutions across Europe, Australia, and North America between 2009 and 2017. We determined the partial response rate to afatinib, types of HER2 mutations, duration of response, time on treatment, and survival.

Results

We collected information on 27 patients with stage IV or recurrent HER2-mutant lung adenocarcinomas treated with afatinib. Of 23 patients evaluable for response, three partial responses were noted (13%, 95% confidence interval 4–33%). In addition, 57% of patients (13/23) had stable disease, and 30% (7/23) had progressive disease. We documented partial responses in patients with HER2 exon 20 insertions, including two with YVMA insertion and one with VAG insertion. Two patients with partial responses were previously treated with trastuzumab and pertuzumab. Median duration of response to afatinib was 6 months (range 5–10); median time on treatment was 3 months (range 1–30) and median overall survival from the date of diagnosis of metastatic or recurrent disease was 23 months (95% CI 18–53 months).

Conclusions

Afatinib is modestly active in patients with HER2-mutant lung adenocarcinomas, including responses after progression on prior HER2-targeted therapies. However, investigations into the biology of HER2-mutant lung adenocarcinomas and development of better HER2-directed therapies are warranted.

2 februari 2016: Bron: Journal of Thoracic Oncology

Uit twee onafhankelijk van elkaar lopende studies met afatinib als monobehandeling als eerstelijnsbehandeling bij vergevorderde longkanker met specifiek uitzaaiingen in de hersenen en bij vergevorderde slokdarmkanker met uitzaaiingen in de hersenen, allen met EGFR positieve expressie blijkt dat afatinib alsnog voor opmerkelijke resultaten zorgt. In vergelijking met de chemo combinaties Alimta en cisplatin of cisplatin en gemzar - gemcitabine blijkt afitinib alleen voor langere progressievrije ziekte te zorgen bij patiënten met hersentumoren (8.2 versus 5.4 maanden; hazard ratio = 0.50, P = .0297), en de overall respons, dus dat de behandeling aansloeg, was veruit superieur voor afitinib in vergelijking met de chemo of placebo (73% versus 25%). Al eerder heeft afatinib bewezen bij longkanker voor goede resultaten te kunnen zorgen, ook die zonder uitzaaiingen in de hersenen. Zie deze grafiek:

afatinib bij longkanker met hersenuitzaaiingen 2

Deze niuewe analyse is een tussenevaluatie van lopende studies waaruit patiënten met hersenuitzaaiingen zijn geselecteerd. Namelijk deze: BIBW 2992 (Afatinib) vs Gemcitabine-cisplatin in 1st Line Non-small Cell Lung Cancer (NSCLC) en deze bij vergevorderde slokdarmkanker: A Phase II Trial of Afatinib in Patients With Metastatic or Recurrent Squamous Cell Carcinoma of Esophagus 

Sleutelpunten uit de studie die een analyse maakte van de twee studies voor specifiek die patiënten met hersenuitzaaiingen vanuit longkanker:

  • 35 uit 345 (10.1%) gerandomiseerd ingedeelde patiënten in de LUX-Lung 3 studie en 46 uit 364 (12.6%) in de LUX-Lung 6 studie hadden hersenuitzaaiingen bij aanvang van de studie en de algemeen voorkomende (Del19 en L858R) EGFR mutaties.
  • De resultaten uit beide studies samengevoegd  gaf afatinib, vergeleken met chemotherapie een statistisch significant betere progressievrije tijd. En de respons, aanslaan van de behandeling, was heel veel beter voor afatinib in vergelijking met chemotherapie.
  • het bijwerkingen profiel voor afatinib bij patiënten met hersenuitzaaiingen lag gelijk aan die bij patiënten zonder hersenuitzaaiingen en waren zonder ernstige veiligheidsrisico's. 

afatinib bij longkanker met hersenuitzaaiingen

Het volledige studieverslag van First-Line Afatinib versus Chemotherapy in Patients with Non–Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases  is gratis in te zien met interessante grafieken.

Hier het abstract van de studie:

Findings from two studies lend support to the clinical activity of afatinib in EGFR mutation–positive patients with NSCLC and asymptomatic brain metastases.

First-Line Afatinib versus Chemotherapy in Patients with Non–Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases

Presented in part at the 15th World Conference on Lung Cancer in Sydney, Australia, October 27–30, 2013.

Martin Schuler, MDcorrespondence
,
Yi-Long Wu, MD
,
Vera Hirsh, MD
,
Kenneth O’Byrne, MD
,
Nobuyuki Yamamoto, MD
,
Tony Mok, MD
,
Sanjay Popat, FRCP
,
Lecia V. Sequist, MD
,
Dan Massey, MSc
,
Victoria Zazulina, MD
,
James C.-H. Yang, MD
Open Access
DOI: http://dx.doi.org/10.1016/j.jtho.2015.11.014

Abstract

Introduction

Metastatic spread to the brain is common in patients with non–small cell lung cancer (NSCLC), but these patients are generally excluded from prospective clinical trials. The studies, phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations (LUX-Lung 3) and a randomized, open-label, phase III study of BIBW 2992 versus chemotherapy as first-line treatment for patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation (LUX-Lung 6) investigated first-line afatinib versus platinum-based chemotherapy in epidermal growth factor receptor gene (EGFR) mutation-positive patients with NSCLC and included patients with brain metastases; prespecified subgroup analyses are assessed in this article.

Methods

For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n = 35 and n = 46, respectively). Post hoc analyses of clinical outcomes was undertaken in the combined data set (n = 81).

Results

In both studies, there was a trend toward improved PFS with afatinib versus chemotherapy in patients with brain metastases (LUX-Lung 3: 11.1 versus 5.4 months, hazard ratio  = 0.54, p = 0.1378; LUX-Lung 6: 8.2 versus 4.7 months, HR = 0.47, p = 0.1060). The magnitude of PFS improvement with afatinib was similar to that observed in patients without brain metastases. In combined analysis, PFS was significantly improved with afatinib versus with chemotherapy in patients with brain metastases (8.2 versus 5.4 months; HR, 0.50; p = 0.0297). Afatinib significantly improved the objective response rate versus chemotherapy in patients with brain metastases. Safety findings were consistent with previous reports.

Conclusions

These findings lend support to the clinical activity of afatinib in EGFR mutation–positive patients with NSCLC and asymptomatic brain metastases.

References

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Drs. Schuler and Wu contributed equally to this work.

Disclosure: Dr. Schuler has received personal fees from Novartis, AstraZeneca, Pfizer, GlaxoSmithKline, and Lilly and grants from Novartis and Boehringer Ingelheim. Dr. Wu has received speaker fees from Eli Lilly, AstraZeneca, Roche, and Sanofi. Dr. Hirsh reports advisory board participation for Boehringer Ingelheim. Dr. O’Byrne has received honoraria for advisory board and speakers’ bureau work; travel, accommodation, and registration expenses for meetings from Boehringer Ingelheim, Merck Sharp Dohme, Lilly Oncology, AstraZeneca, Roche, Pfizer and BMS; and writing assistance from Boehringer Ingelheim, Pfizer, and BMS. Dr. Mok has received personal fees from AstraZeneca, Roche/Genentech, Lilly, Merck Serono, Eisai, BMS, AVEO, Pfizer, Boehringer Ingelheim, Novartis Pharmaceuticals, GlaxoSmithKline, Clovis Oncology, Amgen, Janssen, BioMarin Pharmaceuticals, SFJ Pharmaceuticals, ACEA Biosciences, and Vertex Pharmaceuticals. Dr. Popat has been a consultant for Boehringer Ingelheim. Dr. Sequist reports that her institution received a grant from Boehringer Ingelheim to support the study; has performed noncompensated consulting for Boehringer Ingelheim, Clovis Oncology, AstraZeneca, Novartis, Merrimack, Taiho, and Genentech; and has received personal fees from Ariad for consulting. Drs. Massey and Zazulina are employees of Boehringer Ingelheim. Dr. Yang has received personal fees for presentations and advisory board participation from Boehringer Ingelheim, AstraZeneca, Roche, Genentech, Chugai, Eli Lilly, and MSD and personal fees for advisory board participation only from Merck Serono, Clovis Oncology, Pfizer, Novartis, Ono pharmaceutical, Astellas, Innopharma, Celgene and Bayer. The remaining author declare no conflict of interest.

Trial registration information located at https://clinicaltrials.gov/ identifiers: NCT01121393, NCT00949650.

© 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

afatinib demonstrated durable responses in some patients with exon 20 insertions. Generally, afatinib demonstrated broad activity across very rare (other) mutations, consistent with preclinical findings

May 2020 Volume 15, Issue 5, Pages 803–815

Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases

James Chih-Hsin Yang, MD, PhDa,∗,'Correspondence information about the author MD, PhD James Chih-Hsin Yang
, 
Martin Schuler, MDb
, 
Sanjay Popat, FRCP, PhDc,d
, 
Satoru Miura, MD, PhDe
, 
Simon Heeke, PhDf
, 
Keunchil Park, MDg
, 
Angela Märten, PhDh
, 
Edward S. Kim, MDi

Abstract

Introduction

Limited clinical data are available regarding the efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs) in patients with NSCLC harboring uncommon EGFR mutations. This pooled analysis assessed the activity of afatinib in 693 patients with tumors harboring uncommon EGFR mutations treated in randomized clinical trials, compassionate-use and expanded-access programs, phase IIIb trials, noninterventional trials, and case series or studies.

Methods

Patients had uncommon EGFR mutations, which were categorized as follows: (1) T790M; (2) exon 20 insertions; (3) “major” uncommon mutations (G719X, L861Q, and S768I, with or without any other mutation except T790M or an exon 20 insertion); (4) compound mutations; and (5) other uncommon mutations. Key end points were overall response rate (ORR), duration of response, and time to treatment failure (TTF).

Results

In EGFR TKI–naive patients (n = 315), afatinib demonstrated activity against major uncommon mutations (median TTF = 10.8 mo; 95% confidence interval : 8.1–16.6; ORR = 60.0%), compound mutations (median TTF = 14.7 mo; 95% CI: 6.8–18.5; ORR = 77.1%), other uncommon mutations (median TTF = 4.5 mo; 95% CI: 2.9–9.7; ORR = 65.2%), and some exon 20 insertions (median TTF = 4.2 mo; 95% CI: 2.8–5.3; ORR = 24.3%). The median duration of response for major uncommon mutations, compound mutations, other uncommon mutations, and some exon 20 insertions was 17.1, 16.6, 9.0, and 11.9 months, respectively. Activity of afatinib was also observed in EGFR TKI–pretreated patients (n = 378). A searchable database of these outcomes by individual genotype was generated.

Conclusions

Afatinib has clinical activity in NSCLC against major uncommon and compound EGFR mutations. It also has broad activity against other uncommon EGFR mutations and some exon 20 insertions. The data support the use of afatinib in these settings.

Alimta, chemo, longkanker, EGFR, ALK, crizotinib, afatinib, Tyrosine kinase remmers, overall overleving, ziektevrije tijd, nivolumab


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