new NICE approved CLL treatment zanubrutinib TA931

[Random78]

nice.org.uk/guidance/ta931

You've probably already heard about this NICE recommended treatment - as always the devil is in the detail - not all are suitable!!

[Newdawn Administrator]

Thanks. Here’s further company information previously posted on the site to assist. All approved treatments strengthen our position.

mcusercontent.com/14f1571ca...

Newdawn

[Skyshark]

Initially after approval of Acalabrutinib for all I was upset by the restricted use of Zanubrutinib.

The 30% of patients that are mCLL+TP53wt and eligible for CIT shouldn't be on Zanubrutinib in UK anyway. Ibrutinib + Venetoclax CAPTIVATE FD trial has 94.5% PFS at 48 months for this group. If that promising result continues to hold up it has potential to be a similar "cure" for this excluded but "easy to treat" group as FCR. CLL14 trial of V+O had PFS 83.7% at 48 months and 72.4% at 60 months, [while Zanubrutinib is 85% at 42 months].

V+O has similar approval restriction as Zanubrutinib but allows application to CDF for everyone else. V+I is approved for everyone.

For "difficult to treat" patients that are uCLL+TP53 aberrations this approval of Zanubrutinib is the better option. SEQUOIA trial for Zanubrutinib "the estimated (PFS) rate at 42 months was 79.4%" for del(17p) but only 70% remain on the trial. For V+I the median was reached at 49 months, V+O median is 47 months. Can't see Zanubrutinib losing 30% PFS in 7 months, maybe around 75% and median around 100 months.

themedicalxchange.com/en/20...

For the other two groups uCLL+TP53wt and mCLL+TP53abr, I think both are allowed Zanubrutinib. uCLL is unsuitable for CIT and TP53abr is in scope. There doesn't seem to be much to chose between [Zanubrutinib], V+I and V+O. PFS @48 months uCLL+TP53wt, [72%], 74.0%, 74.6% (median 66.6 months) and for mCLL+TP53abr [80~85% (@42 months)], 77.8%,100% (75% @49 months - only 5 patients and one was censored before 48 months). The BTKi has to perform better as it's one time only, the V+I and V+O can be followed by BTKi. CAPTIVATE trial issues result reports 3 months before follow ups and and 9 months after previous follow up. At every follow up, the KM plots for V+I dip below those for V+O. I expect the "real world" results to track those dips and make V+O the better choice if the patient can withstand the addition IV's of Obinutuzumab and additional blood tests if high risk of TLS.

[note] There is degree of uncertainty for PFS of Zanubrutinib as a large number of the cohort are censored before 42 and 48 months. As they pass though follow-ups there may be more found to be progressing which will reduce the PFS, or none will be found to be progressing which will improve the PFS.

NICE Zanubrutinib recommendation

[SeymourB in reply to Skyshark]

Skyshark -

Issues to consider when choosing between V+I and V+O:

1. Heart side affects with V+I .

2. Additional immune suppression with V+O

=seymour=

[JEEA]

Interesting to read this. Thank you. I have a haematologist who seems anxious to get me on treatment. My lymphocytes have been going steadily up with each blood test, but are not doubling in 6 months, now am I losing weight nor seem to any prominent lymph nodes--just small ones on in my armpits that have been there from when I began W and W 5 years ago. I do get tired at times--but I am almost 80 and pretty active.

Two months ago, she wrote to my GP that I would probably need to start treatment in two months, she talked possible treatments at length with me and then sent me off for a CT Scan as well as a blood test to check if I was TP53 deleted.

I have just had my follow up appointment a week ago--and was relieved (but not surprised) to hear that my scan was clear--just one more small node--and I was not 53 deleted. So worry over for now. She said she thought that a sign when I need treatment might be becoming anemic......

But she did say that the hospital could not get Zanubrutinib as it was not yet NICE approved, as I think that would be my preferred treatment at age almost 80. But it seems that it now is approved. Reading through--I think I would be suitable..... but not clear..... Don't quite understand their caveats... How would we know if "there is no 17p deletion or TP53 mutation, and fludarabine plus cyclophosphamide and rituximab (FCR), or bendamustine plus rituximab (BR) is unsuitable " ? Are the other treatments cheaper? Or is there a health reason? Very unclear.

I wonder if you or others have a clearer understanding about when one is suitable or not?

Eleanor

[Skyshark in reply to JEEA]

Being over 65, FCR wouldn't be considered, BR is suitable for over 65's. Doctors will consider you unsuitable for CIT due to IgHV unmutated but the NICE recommendations don't look at IgHV status so deem you suitable for BR. Doctors will offer you other drugs that are available to all and not BR. Continuous Acalabrutinib, short duration Venetoclax + Obinutuzumab (with CDF funding) or Venetoclax + Ibrutinib.

Don't get too hung up on Zanubrutinib, it's only just been approved and the NICE approval in section 4 Implementation states they have up to three months to make it available. Acalabrutinib has fewer side effects, is better tolerated and is available for all but maybe marginally less effective.

At UK list prices from NICE approval documents, excluding VAT (NHS gets commercial discount).

V+O £76,785, 12 cycles, 48 weeks, V+I £118,267, 15 cycles, 60 weeks. Continuous BTKi monotherapies, Zanubrutinib £59,965/pa, Acalabrutinib £61,551/pa and Ibrutinib £55,954.50/pa.

The overall median progression free survival for V+O is about 76 months, £12,124/pa. After progression is detected there can be up to a year until next treatment starts £10,470/pa. There are additional costs for blood tests on initial Obinutuzumab and Venetoclax ramp up, 9 days in chemo chair and 22% have 10 days/7 nights as inpatient.

I expect the overall median PFS for V+I will be similar to V+O, 76 months, £18,674/pa. To start of next treatment £16,127/pa. There are additional costs for blood tests on Venetoclax ramp up. About 2% have 6 days/4 nights as inpatient.

When progression is found on BTKi treatment it is usually a rush to the next treatment. 76 months of Zanubrutinib £379,778, Acalabrutinib £379,778 or Ibrutinib £354,378.

Beats me how any continuous monotherapy gets approval on costs, other than it's a vital treatment for anyone with renal problems that can't have Venetoclax.

[JEEA in reply to Skyshark]

Thanks so much for such a comprehensive reply, Sykshark. I had no idea how expensive these drugs are. Makes one pleased to be able to pay taxes to help fund our beleaguered NHS.

I'm curious how you know such detailed information about the cost of these drugs? Did you work in the NHS? So on cost grounds alone, one should opt for a non-continuous monotherapy. Having said that, at my age, for me, I think I'd prefer that once or twice daily pill........

But pill or infusions, don't like the thought of putting these powerful drugs into my body until it is absolutely necessary.

Eleanor

[Skyshark in reply to JEEA]

It's kinda lost in there. The prices are in the NICE recommendations.

It's not like chemo drugs, they indiscriminately affect every cell in the body that is dividing, hair and nail growth, skin and gut lining are replaced by cell division nearly daily. They just hope to kill the more rapidly dividing cancer cells before having too much affect on the patient.

These novel targeted drugs match the pattern of certain proteins found on and in CLL B-cells and bond to them. CD20 is used to attach monoclonal antibodies that tag the cell for destruction. BTKi blocks a signal path that keeps a cell alive and BCL-2 prevents the mitochondria working to power the cell so the cell dies. The pattern these match is like a complex key and isn't found in many other places other than the cancerous B-cell.

[JEEA in reply to Skyshark]

Thank you. Goodness, you do know a lot about how these drugs work, about which I hadn't thought to ask.

Are you a biochemist? We are visiting two biochemists in Cambridge at Christmas, so will talk to them as well--one a professor there and his wife in research. For me, it is good to know what happens when we put these powerful drugs into our bodies. Eleanor

[Skyshark in reply to JEEA]

No, I'm a former jet engine FEA engineer and sometime shade tree spanner monkey.

[JEEA in reply to Skyshark]

Goodness-- well engineers want to know how things work -- and MOST important for jet engines!!! Thank goodness we have minds like yours! AS to 'shade tree spanners'.......?????