Evre IV kolon kanserinde yeni tedavi seçeneği olarak sotorasib ve panitumumab kombinasyonu

Evre IV kolon kanserinde yeni tedavi seçeneği olarak sotorasib ve panitumumab kombinasyonu

Kolon kanseri kadın ve erkeklerde sık görülen bir kanser türü.

Evre IV hastalıkta tedavi öncesi karar vermeden önemli klinik ve genetik parametrelere bakılır. Tümörün sağ kolon ya da sol kolondan köken alıp almaması tedavide yol gösterici olduğu gibi, KRAS, NRAS ve BRAF mutasyonu ve HER2 ekspresyonun olup olmaması önemli bir seçenek.

Diğer önemli bir husus, yaklaşık hastaların %5 oranında görülen Mikrosatellit instabilite olup olmaması. Mikrosatellit instabilite patolojik bloklarda immün histokimyasal boyalarla tümör supresyon genlerin aktivitesi sonu ortaya çıkan protein ekspresyonlarının (MLH1, PMS2, MSH2, MSH6) kaybının gösterilmesi ya da PCR ile direk gen kayıplarının saptanması ile belirlenir.

Mikrosatellit instabilite olan hastalar immünoterapiye yanıt oranları %50 yüksek ve yanıt alınan hastalar uzun dönem hastalıksız yaşayabilmektedir.

Son yapılan çalışma (CodeBreaK 300), KRAS G12C mutasyonu olan hastalar için yeni bir seçeneği gündeme soktu.

KRAS G12C mutasyonu evre IV kolon kanserinde yaklaşık olarak %3-4 oranında görülür. Sotorasib ve panitumumab kombinasyonu tedavi seçeneğini tüketmiş bu grup hastada standart tedaviye (trifluridine-tipiracil ve regorafenib) göre hastalıksız süre ve klinik yarar oranın daha iyi olduğu saptandı.

Sotorasib dozu 940 mg çıkarılan hasta grubunda yarar daha belirgin. Sotorasib, KRAS G12C mutasyonu sonrası artan tirozin kinaz aktivitesini inhibe eden ve oral alınan bir molekül. Panitumumab EGFR reseptörünü bloke eden damardan verilen antikor yapısında bir ilaç.

Bu kombinasyonun en büyük handikabı fayda- maliyet oranı arasındaki dengesizlik ve yan etkiler. Etki yüksek dozda görülmekte ve doz artıkça yan etki artmaktadır.

Fakat mutasyona sepesifik bir molekülün başarılı olması, gelecek daha etkili ve tolere edilebilen moleküler için bir öncü olacaktır. Bu yönüyle büyük bir başarı ve dönüm noktasıdır.

Kaynak

KRAS G12C, a driver mutation, occurs in approximately 3% of patients with metastatic colorectal cancer and may be associated with a poor prognosis. In patients who experience disease progression on standard initial therapies, treatment with trifluridine-tipiracil or regorafenib—which were used in the control arm of CodeBreaK 300—have shown limited efficacy, and better late-line therapies are lacking.

About CodeBreaK 300

In the open-label trial, more than 150 patients enrolled from sites in 12 countries were randomly assigned to one of the following three arms:

Sotorasib at 960 mg once daily (standard dose) plus panitumumab at 6 mg/kg every 2 weeks (n = 53)

Sotorasib at 240 mg once daily plus panitumumab (n = 53)

Standard therapy with investigator’s choice of either trifluridine/tipiracil at 35 mg/m2 on days 1–5 and 8–12 every 28 days (n = 37) or regorafenib at 160 mg once daily on days 1–21 every 28 days (n = 14).

Approximately 85% of patients had received two or more prior lines of therapy, but none included a KRAS-targeted agent. Right-sided tumors were more common in the 960-mg sotorasib arm (45%) than the 240-mg sotorasib arm (32%) or the control arm (30%). The primary endpoint was progression-free survival by blinded independent central review.

Improvements With Combination Therapy

At a median follow-up of 7.8 months, patients treated with sotorasib at 960 mg plus panitumumab had a median progression-free survival of 5.6 months vs 2.2 months with standard therapy (hazard ratio [HR] = 0.49; P = .006). With the lower sotorasib dose of 240 mg plus panitumumab, median progression-free survival was 3.9 months (HR = 0.58; P = .03). “Progression-free survival by blinded independent central review favored sotorasib plus panitumumab across key patient subgroups,” Dr. Pietrantonio said.

The objective response rate was 26% with 960 mg of sotorasib plus panitumumab (including one complete response), 6% with 240 mg of sotorasib plus panitumumab, and 0% with standard treatment. Disease control rates were 72%, 68%, and 46%, respectively, and the median duration of response was 4.4 months in the 960-mg sotorasib group. Tumor shrinkage of any level was observed in 81%, 57%, and 20%, respectively. Overall survival results were immature at the time of the analysis.

Safety

Treatment-related grade ≥ 3 adverse events occurred in 36%, 30%, and 43% of patients given 960 mg of sotorasib, 240 mg of sotorasib, and standard care, respectively. Skin-related toxicities (rash and dermatitis acneiform) and hypomagnesemia were the most common adverse events seen with sotorasib plus panitumumab, whereas neutropenia and nausea were the most common adverse events reported with standard therapies. Treatment-related serious adverse events occurred in 6%, 0%, and 8% of patients in the three groups and led to discontinuation of any study drug in 4%, 2%, and 2%, respectively.

“No new safety concerns were observed. These results, along with previous data from non–small cell lung cancer, support sotorasib at 960 mg as the sotorasib dose for use in metastatic colorectal cancer,” Dr. Pietrantonio concluded.

DISCLOSURE: The study was funded by Amgen. Dr. Pietrantonio reported financial relationships with Amgen, Astellas Pharma, Bayer, Bristol Myers Squibb, GSK, Merck KGaA, Merck Sharp & Dohme, Pierre Fabre, Johnson & Johnson, Takeda, and Servier.

REFERENCES

1. Pietrantonio F, Salvatore L, Esaki T, et al: Sotorasib plus panitumumab versus standard-of-care for chemorefractory KRAS G12C–mutated metastatic colorectal cancer: CodeBreaK 300 phase III study. ESMO Congress 2023. Abstract LBA10. Presented October 22, 2023.

2. Fakih MG, Salvatore L, Esaki T, et al: Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. N Engl J Med. October 22, 2023 (early release online).