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Phase 3 SONIA Trial Challenges the Routine Practice of Using a 1st Line CDK4/6 Inhibitor

bestbird Member Posts: 232

Those with HR+, HER2- MBC may find this interesting!

The Phase 3 SONIA study of 1,050 patients with HR+, HER2- MBC evaluated progression free survival (PFS) and overall survival (OS) from the initiation of first line treatment through failure of second line treatment. It compared two groups of patients.  One group took the current first line standard-of care-treatment consisting of a combination of a CDK4/6 inhibitor with an aromatase inhibitor (followed by Faslodex as second-line treatment after progression). The second group started with an aromatase inhibitor alone, followed by a combination of a CDK4/6 inhibitor with Faslodex after progression on initial treatment.

As disclosed at ASCO 2023, the study determined that there was no statistically significant difference in time to progression and OS through second-line therapy between the two groups. Median OS through second line treatment reached 45.9 months when a CDK4/6 inhibitor was used in the first line, and 53.7 months when a CDK4/6 inhibitor was used in the second line (P = .83).  (Anne's note: nearly 8 months' difference in OS sounds pretty significant to me!)

Patients who received a CDK4/6 inhibitor up-front remained on it for a median of 24.6 months until moving to second line treatment, whereas patients who received a CDK4/6 inhibitor in the second line took it for a median of 8.1 months until treatment failure - a 16.5 month difference.  Because patients taking the CDK4/6 inhibitor as first line therapy remained on it much longer than patients taking it in the second line setting, they experienced a 42% increase in the incidence of grade 3/4 toxicity and an increase in drug expenditure of approximately $200,000 per patient.

According to Gabe Sonke, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, the SONIA results warrant rethinking of the current "CDK4/6 inhibitor in the first line setting for all" paradigm.  And Daniel Stover, MD, of the Ohio State University Comprehensive Cancer Center, agreed that the SONIA trial asks the important question of whether all patients need to start with a CDK4/6 inhibitor as first-line therapy because identifying the ‘right size’ therapy for patients with HR+, HER2- MBC is highly important.

The SONIA study has some limitations.  It reflects state-of-the-art treatment when the trial was initiated in 2017 but now may be considered somewhat dated. For example, more than 90% of patients in the study received Ibrance as the CDK4/6 inhibitor, which is currently considered the least attractive CDK4/6 inhibitor to use in the first line because of its relative lack of OS benefit. Moreover, in the second line setting, other treatment options are now available such as Piqray plus Faslodex and Elacestrant, along with other emerging agents and combinations.

In conclusion, as Dr. Sonke further commented, by conducting randomized clinical trials such as SONIA that evaluate shorter treatment courses, lower doses, or less frequent administration, researchers can determine the optimal treatment that minimizes harmful side effects while maintaining the therapeutic benefits. This approach can significantly reduce the toxicity of medications while making effective drugs more accessible to patients who would otherwise find them unaffordable. Furthermore, the costs of these trials can be covered by the savings achieved through the less-expensive treatments used in the study - the SONIA study saved approximately 25 million Euros on drug expenditure during the trial which may entice insurance companies and governments that are paying for patient care to fund these trials since they become self-funding.



  • irishlove
    irishlove Member Posts: 530

    Bestbird Hello Ann and thank you for posting these astounding results from the study. It is so wonderful to hear from you and appreciate you for continuing to keep us informed.

    I hope you are still finding more of those sweet moments that you spoke of.

    Forever in your debt for bringing forth the facts in your well written book on breast cancer.

    Irishlove aka Laurel

  • bestbird
    bestbird Member Posts: 232

    Laurel, thank you for your lovely words! I'm delighted to say that I've been feeling better and am happy to be able to share encouraging news such as this study!

    With best wishes.

  • cure-ious
    cure-ious Member Posts: 2,760

    Wonderful to "see" you Anne!!!

    So, in this trial, there is no comparative arm for those getting a CDK4,6i in both arms, which one might expect to do better still, no?

    for me, now, with the cancer vaccines doing so well (Moderna just updated their melanoma trial, benefit of the vaccine added to Keytruda was 65% compared to Keytruda alone, whereas previously it was 44% better) and the BioNTech about to do a 10K patient trial for most comers in the UK, all I care about is doing "well enough" until these approaches or other TILs are more widely available. e.g., hoping we see strategies that give much bigger boosts for the later lines…

  • aprilgirl1
    aprilgirl1 Member Posts: 787

    Anne aka Bestbird - so wonderful to see you post, and thank you for keeping us up to date, as Irishlove said so well.

    I also appreciate input from Cure-ious - I am also hoping to just stay well enough on Ibrance/fulvestrant until better options are available.

  • sondraf
    sondraf Member Posts: 1,631

    This is interesting - i was reading somewhere (FT maybe) that the UK risks falling behind in clinical trials administration due to issues of affordability, clinical time availability, and all the bureaucracy from Brexit. That's beside the greater point about CDK 4/6 timing. Ill have to look at that further - what would that have meant for de novo folks and if any were included.

    @cure-ious apparently the mRNA vaccine test will be starting with Stage II and III bowel cancer patients in Birmingham, testing vaccine vs watch and wait (2 May latest update on this trial):

  • cure-ious
    cure-ious Member Posts: 2,760

    Sondra, It's interesting that they are starting with specific cancers, rather than opening it up to all types. So, early stage, high risk, colorectal cancer- sounds like a reasonable place to start, given these folks have few options to prevent it coming back. I read it will be available to stage IV patients, but am curious about the protocol they will use, given that early stage cancers there is a tumor sample they can use to analyze for neoantigens, whereas for metastatic cancers they presumably will need to go in and cut out a metastatic tumor, as they did for Nicole. The vaccine relies on patients to raise their own antibodies to a finite number of neoantigens that are expressed from the vaccine, whereas for TILs, they just extract the antibodies the patient already has in their tumor, activate them and grow them up to high numbers and infuse into an immune-depleted patient. So if it is a battle between cancer and immune cells, the TILs would seem to have the leg up there. However, both approaches you would think should also need something to get rid of the immune cells protecting the mets. But we gotta start somewhere, and hopefully many of these 10K trials will include metastatic patients to that we can see how well it works, sooner than later..