9 januari 2023: zie ook literatuurlijst voeding en middelen en weinig belastende behandelingen specifiek voor darmkanker van arts-bioloog drs. Engelbert Valstar.

9 januari 2023: Zie ook dit studierapport over de verschillende vormen van KRAS mutaties.

9 januari 2023: Bron January 5, 2023 N Engl J Med 2023; 388:44-54

Adagrasib (Krazati) met of zonder cetuximab bij patiënten met zwaar voorbehandelde darmkanker met gemuteerde KRAS G12C geeft hoopvolle resultaten. Adagrasib met of zonder cetuximab vertoonde antitumoractiviteit, met een objectief responspercentage van respectievelijk 19% en 46% in de monotherapie- en combinatiebehandelingsgroepen.
Uit een kleinschalige fase I/II studie waren mediane progressievrije overleving en totale overleving respectievelijk 5,6 maanden en 19,8 maanden met adagrasib als monotherapie en waren respectievelijk 6,9 en 13,4 maanden met de combinatie behandeling van cetuximab en Adagrasib (Krazati).

Ook longkankerpatiënten met KRAS G12C hadden baat bij Adagrasib (Krazati):

Ook longkankerpatiënten met KRAS G12C hadden baat bij Adagrasib (Krazati):

Op het moment van de afsluiting van de gegevens konden 15 van de 16 patiënten met KRASG12C-mutant NSCLC bij 600 mg tweemaal daags worden beoordeeld op respons. Na een mediane follow-uptijd van 19,6 maanden was het bevestigde totale responspercentage 53,3% (95% BI, 26,6 tot 78,7; Fig Fig3)3) en de mediane DOR was 16,4+ maanden (95% BI, 3,1 tot niet schatbaar; bereik, 2,8-16,9 maanden). Twee reacties traden op in latere cycli bij patiënten die langer dan 10 maanden werden behandeld. Vier patiënten hadden aanhoudende responsen met een duur van respectievelijk 16,9, 12,6, 5,4 en 2,8 maanden op het moment van de data-cutoff (Figuur (Fig33).

Van de 16 patiënten met KRASG12C-mutant NSCLC die werden ingeschreven en behandeld bij de RP2D, was de mediane PFS 11,1 maanden (95% BI, 2,6 tot niet te schatten; bereik, 0-22,4+ maanden). Kaplan-Meier-schattingen van PFS na 6 en 12 maanden waren respectievelijk 64,3% (95% BI, 34,3 tot 83,3) en 50,0% (95% BI, 22,9 tot 72,2) (gegevenssupplement). De mediane OS was NR (95% BI, 3,1 tot niet te schatten) en varieerde van 2,1 tot 23,4+ maanden (gegevenssupplement). OS-percentages voor deze patiënten na 6 en 12 maanden waren respectievelijk 73,3% (95% BI, 43,6 tot 89,1) en 66,7% (95% BI, 37,5 tot 84,6). Negen van de 16 patiënten waren in leven op het moment dat de gegevens werden afgesneden op 15 augustus 2021, waaronder vijf patiënten die nog in behandeling waren.

Zie dit studierapport (abstract onderaan artikel) :

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1)

Uit het abstract van de darmkankergroepen vertaald:

Op 16 juni 2022 hadden in totaal 44 patiënten adagrasib gekregen en 32 hadden de combinatiebehandeling met adagrasib en cetuximab gekregen, met een mediane follow-up van respectievelijk 20,1 maanden en 17,5 maanden.
In de monotherapiegroep (43 evalueerbare patiënten) werd een respons gemeld bij 19% van de patiënten (95% betrouwbaarheidsinterval , 8 tot 33).
De mediane responsduur was 4,3 maanden (95% BI, 2,3 tot 8,3) en de mediane progressievrije overleving was 5,6 maanden (95% BI, 4,1 tot 8,3).
In de combinatietherapiegroep (28 evalueerbare patiënten) was de respons 46% (95% BI, 28 tot 66).
De mediane responsduur was 7,6 maanden (95% BI, 5,7 tot niet schatbaar) en de mediane progressievrije overleving was 6,9 maanden (95% BI, 5,4 tot 8,1).
Het percentage graad 3 of 4 behandelingsgerelateerde bijwerkingen was 34% in de monotherapiegroep en 16% in de combinatietherapiegroep. Er werden geen bijwerkingen van graad 5 waargenomen.

Het abstract van deze studie staat hieronder. Voor het volledige studierapport moet worden betaald.

Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C

Rona Yaeger, M.D.,
Jared Weiss, M.D.,
Meredith S. Pelster, M.D.,
Alexander I. Spira, M.D., Ph.D.,
Minal Barve, M.D.,
Sai-Hong I. Ou, M.D., Ph.D.,
Ticiana A. Leal, M.D.,
Tanios S. Bekaii-Saab, M.D.,
Cloud P. Paweletz, Ph.D.,
Grace A. Heavey, B.A.,
James G. Christensen, Ph.D.,
Karen Velastegui, B.Sc.,

Abstract

BACKGROUND

Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.

METHODS

In this phase 1–2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety.

RESULTS

As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval , 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed.

CONCLUSIONS

Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249. opens in new tab.)

Supported by Mirati Therapeutics and by a grant (P30 CA 008748) to the Memorial Sloan Kettering Cancer Center from the National Cancer Institute.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on December 21, 2022, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the patients and their families and caregivers; the trial team members at each site; Rachel Verdon of Ashfield MedComms for writing support with a previous version of the manuscript; and Linh Alejandro and Aditya Shetty of Mirati Therapeutics for contributions to the development of the manuscript.

Author Affiliations

From the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.Y.); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill (J.W.); Sarah Cannon Research Institute, Tennessee Oncology, Nashville (M.S.P.); Virginia Cancer Specialists, NEXT Oncology–Virginia, Fairfax (A.I.S.); US Oncology Research, the Woodlands (A.I.S.), and Mary Crowley Cancer Research, Dallas (M.B.) — both in Texas; the University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange (S.-H.I.O.), and Mirati Therapeutics, San Diego (J.G.C., K.V., T.K., H.D.-T.) — all in California; the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta (T.A.L.); Medical Oncology, Mayo Clinic, Phoenix, Arizona (T.S.B.-S.); Belfer Center for Applied Cancer Science and the Department of Medical Oncology, Dana–Farber Cancer Institute (C.P.P., G.A.H.), and the Department of Medicine, Division of Hematology–Oncology, Massachusetts General Hospital (S.J.K.) — both in Boston.

Dr. Klempner can be contacted at sklempner@partners.org or at the Department of Medicine, Division of Hematology–Oncology, Massachusetts General Hospital, Boston, MA 02114. Dr. Yaeger can be contacted at yaegerr@mskcc.org or at the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.

A complete list of the KRYSTAL-1 trial investigators is provided in the Supplementary Appendix, available at NEJM.org.

QUICK TAKE VIDEO SUMMARYAdagrasib with or without Cetuximab in Colorectal Cancer

Adagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRASG12C mutation.

2022 Aug 10; 40(23): 2530–2538.

Published online 2022 Feb 15. doi: 10.1200/JCO.21.02752

PMCID: PMC9362872

PMID: 35167329

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1)

Sai-Hong Ignatius Ou, MD, PhD, corresponding author

1 Pasi A. Jänne, MD, PhD, 2 Ticiana A. Leal, MD, 3 Igor I. Rybkin, MD, PhD, 4 Joshua K. Sabari, MD, PhD, 5 Minal A. Barve, MD, 6 Lyudmila Bazhenova, MD, 7 Melissa L. Johnson, MD, 8 Karen L. Velastegui, BSc, 9 Cornelius Cilliers, PhD, 9 James G. Christensen, PhD, 9 Xiaohong Yan, PhD, 9 Richard C. Chao, MD, 9 and Kyriakos P. Papadopoulos, MD 10

Author information Article notes Copyright and License information Disclaimer

Associated Data

Data Availability Statement

PURPOSE

Adagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRASG12C. We report results from a phase I/IB study of adagrasib in non–small-cell lung cancer, colorectal cancer, and other solid tumors harboring the KRASG12C mutation.

MATERIALS AND METHODS

Patients with advanced KRASG12C-mutant solid tumors were treated with adagrasib 150 mg orally once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg orally twice a day using an accelerated titration design, which transitioned to a modified toxicity probability interval design when a predefined degree of toxicity was observed or target adagrasib exposure was achieved. Safety, pharmacokinetics, and clinical activity were evaluated.

RESULTS

Twenty-five patients were enrolled and received at least one dose of adagrasib. The recommended phase II dose (RP2D) was 600 mg twice a day on the basis of safety, tolerability, and observed pharmacokinetics properties. No maximum tolerated dose was formally defined. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluable KRASG12C-mutant non–small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response. The median duration of response was 16.4 months (95% CI, 3.1 to not estimable). The median progression-free survival was 11.1 months (95% CI, 2.6 to not estimable). One of two patients with KRASG12C-mutant colorectal cancer treated at 600 mg twice a day achieved a partial response (duration of response, 4.2 months). At the RP2D, the most common treatment-related adverse events (any grade) were nausea (80.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3-4 treatment-related adverse event was fatigue (15.0%).

CONCLUSION

Adagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRASG12C mutation.

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adagrasib, KRAS G12C, darmkanker, longkanker