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16 mei 2020: FDA heeft nu al goedkeuring gegeven aan selpercatinib voor longkanker en schildklierkanker mdet zogeheten RET genmutaties of fusies. Op basis van de uitstekende resultaten zoals hieronder ook beschreven. Klik op de volgende link voor de details: FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions 

Op de website van de producent staat ook uitgebreide omschrijving van de

9 februari 2020: lees ook dit artikel: 

https://kanker-actueel.nl/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

11 september 2019: Bron: longkankerconferentie Barcelona

Uit de resultaten van een fase I/II studie LIBRETTO-001 werden op de wereldconferentie over longkanker in Barcelona bijzonder positieve resultaten gepubliceerd voor een behandeling met Selectiatinib (LOXO-292) bij zwaar voorbehandelde niet-kleincellige longkanker met een RET fusie-positieve mutatie. 68 procent van de deelnemende patienten (N = 101 ) bereikte een zogeheten objectieve respons (minimaal een gedeeltelijke remissie van 50 procent of meer). 

Bij patienten die nog niet waren behandeld maar wel een diagnose hadden van RET fusie - positieve niet-kleincellige longkanker (NSCLC) (n=34), resulteerde de behandeling met selpercatinib in een 85% (95% confidence interval 69% - 95%) objectieve response. Die alleen maar beter kan worden omdat de meeste patienten , eenmaal een remissie bewerkstelligd dit bleven houden. Een bijzonder goed resultaat dus.

RET-fusie mutatie wordt inmiddels gezien als een van de vier belangrijkste mutaties bij longkanker en past in het rijtje van EGFR, ALK en ROS1 mutaties. Bij longkanker is een DNA- en receptorenonderzoek op in ieder geval die mutaties inmiddels verplicht. De RET-fusie mutatie komt daar nu bij zeggen de onderzoekers. Want de FDA heeft al eerder toestemming gegeven voor onderzoek naar effecten van RET-fusie remmer Selectiatinib (LOXO-292)

Kernpunten uit de studie zoals producent LILY die op hun website melden:


- 68 procent objectief responspercentage (ORR) (n = 105) van RET-fusie-positieve NSCLC-patiënten die eerder chemotherapie hadden gekregen
- 85 procent objectief responspercentage (ORR) bij nog niet behandelde RET-fusie-positieve NSCLC-patiënten (redactie: dus als eerstelijns bij diagnose van longkanker met RET-fusie postitief) 

- Eerste en enige RET-remmer die een robuuste CZS-ORR aantoont (91%).Duurzame remissies gemeten aan de hand van zowel de responsduur als de progressievrije overleving
- Goed getolereerd veiligheidsprofiel; laag percentage van patienten (N = 531) die stopten met de behandeling (1,7%) wegens behandelingsgerelateerde bijwerkingen

Hier de studie gegevens uit de presentatie van het abstract:

In the registration dataset composed of the first 105 enrolled RET fusion - positive patients with NSCLC who had undergone prior platinum-based chemotherapy, selpercatinib treatment resulted in a 68% (95% confidence interval 58% - 76%) objective response rate.

This population was heavily pretreated (median of three prior systemic regimens; 55% treated previously with an anti – programmed death (PD) 1/PD – ligand 1 (L1) antibody, and 48% treated previously with at least one multikinase inhibitor). The objective response rate was similar regardless of prior therapy.

Up to 50% of RET fusion - positive NSCLCs can metastasize to the brain, and in the subset of patients with brain metastases in the registrational dataset, selpercatinib treatment demonstrated a CNS (central nervous system) objective response rate of 91% (95% confidence interval 59% - 100%).

As of the data cutoff in June 2019, the median duration of response was 20.3 95% confidence interval 13.8 - 24.0) months. Median progression-free survival was 18.4 (95% confidence interval 12.9 - 24.9) months.

Since the majority of patients remain in response or are progression-free as of the data cutoff date, these medians will continue to mature over time.

In a safety analysis of all 531 patients enrolled to LIBRETTO-001, selpercatinib was well tolerated, with only nine patients (1.7%) discontinuing therapy due to treatment-related toxicity.

The most commonly observed adverse events, regardless of attribution, were dry mouth, diarrhea, hypertension, increased liver enzymes, fatigue, constipation, and headache.

In treatment-naïve patients with RET fusion - positive NSCLC (n=34), selpercatinib treatment resulted in an 85% (95% confidence interval 69% - 95%) objective response rate.

Median duration of response and progression-free survival were not reached in this treatment-naïve population, as the majority of patients remain in response or are progression-free.

The LIBRETTO trial includes a dose escalation (phase 1) and a dose expansion (phase 2) phase. The primary endpoint of the phase 2 portion is objective response rate and secondary endpoints of duration of response, progression-free survival, and safety.

Op de website van LILY staat een en ander nog uitgebreider.

Het abstract zoals gepresenteerd in Barcelona staat in dit abstractenoverzicht.

Food and Drug Administration (FDA) approved Retevmo™ (selpercatinib, 40 mg & 80 mg capsules), the first therapy specifically indicated for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), and the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, or advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)

On May 8, 2020, the Food and Drug Administration granted accelerated approval to selpercatinib (RETEVMO, Eli Lilly and Company) for the following indications:

  • Adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC);
  • Adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy;
  • Adult and pediatric patients ≥12 years of age with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).

Efficacy was investigated in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001) in patients whose tumors had RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either next generation sequencing, polymerase chain reaction, or fluorescence in situ hybridization. The main efficacy outcome measures were overall response rate (ORR) and response duration determined by a blinded independent review committee using RECIST 1.1.

Efficacy for RET-fusion-positive NSCLC was evaluated in 105 adult patients, previously treated with platinum chemotherapy. The ORR was 64% (95% CI: 54%, 73%); 81% of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 39 patients who never received systemic treatment. The ORR for these patients was 85% (95% CI: 70%, 94%); 58% of responding patients had responses lasting 6 months or longer.

Efficacy for advanced or metastatic RET-mutant MTC was investigated in adults and pediatric patients (≥12 years of age). The trial enrolled patients previously treated with cabozantinib, vandetanib, or both, and patients who had not received these drugs. The ORR for the 55 previously treated patients was 69% (95% CI: 55%, 81%); 76% of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 88 patients not previously treated with an approved therapy for MTC. The ORR for these patients was 73% (95% CI: 62%, 82%); 61% of responding patients had responses lasting 6 months or longer.

Efficacy for RET fusion-positive thyroid cancer was evaluated in adults and pediatric patients (≥12 years of age). The trial  enrolled 19 patients who were radioactive iodine-refractory (if appropriate) and had received another prior systemic treatment, and 8 patients who were RAI-refractory and had not received any additional therapy. The ORR for the 19 previously treated patients was 79% (95% CI: 54%, 94%); 87% of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 8 patients who received RAI and no other subsequent therapy. All 8 patients responded (95% CI: 63%, 100%) and 75% had responses lasting 6 months or longer.

The most common adverse reactions, including laboratory abnormalities, (≥ 25%) were increased aspartate aminotransferase, increased alanine aminotransferase, increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelets, increased total cholesterol, rash, decreased sodium, and constipation.

The recommended selpercatinib dose is weight based—120 mg for patients less than 50 kg, and 160 mg for those 50 kg or greater. Selpercatinib is taken orally twice daily with or without food; or with food when co-administered with a proton pump inhibitor.

View full prescribing information for RETEVMO.


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