Since my role as an original rattie in an adjuvant arm of Stage IV melanoma peeps using MDX1106 - today's nivolumab (Opdivo) - in 2010, I haven't stopped yelling about the need for adjuvant treatment for other melanoma patients for one minute!!! Here are 9 zillion pertinent posts from this blog: Adjuvant therapy for melanoma I am particularly proud of yelling this in 2017 -
FRIDAY, OCTOBER 13, 2017
Adjuvant treatments in melanoma - They WORK!!! Now, let's make sure people can get them!!!!!
It was certainly good news when the FDA (FINALLY!!!) approved ipi as an adjuvant treatment for melanoma. And....it works! ASCO 2017: Ipi 3 mg vs 10 mg in advanced melanoma and as adjuvant
We also KNOW that anti-PD-1 works EVEN BETTER, with fewer side effects, as an adjuvant treatment in melanoma. The trial that I and my fellow ratties started in 2010 proved that...and so have other studies since: Nivo better than ipi as adjuvant treatment for melanoma! Surprise, surprise, surprise!!!
We also KNOW that BRAF/MEK inhibitors are extremely effective as an adjuvant therapy in patients with BRAF positive melanoma: 2016: Straight Outta Boston!!! Latest melanoma research ~
It is with a mixture of satisfaction, frustration, smug back patting, and hope - that I share these recent results that CONFIRM - ADJUVANT THERAPIES WORK FOR MELANOMA!!!!!
Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. Drummer, Hauschild, Saninami, et al. New England Journal of Medicine. September 17, 2020.
In the previously reported primary analysis of this phase
3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly
longer relapse-free survival than placebo in patients with resected stage III
melanoma with BRAF V600E or V600K mutations. To confirm the stability of the
relapse-free survival benefit, longer-term data were needed.
We randomly assigned 870 patients who had resected stage
III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral
dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily)
or two matched placebos. The primary end point was relapse-free survival. Here,
we report 5-year results for relapse-free survival and survival without distant
metastasis as the site of the first relapse. Overall survival was not analyzed,
since the required number of events to trigger the final overall survival
analysis had not been reached.
The minimum duration of follow-up was 59 months (median
patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for
placebo). At 5 years, the percentage of patients who were alive without relapse
was 52% with dabrafenib plus trametinib and 36% with placebo. The percentage of
patients who were alive without distant metastasis was 65% with dabrafenib plus
trametinib and 54% with placebo. No clinically meaningful
between-group difference in the incidence or severity of serious adverse events
was reported during the follow-up period.
In the 5-year follow-up of a phase 3 trial involving
patients who had resected stage III melanoma with BRAF V600E or V600K
mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib
resulted in a longer duration of survival without relapse or distant metastasis
than placebo with no apparent long-term toxic effects.
Good. Now. Enough with the placebo crapolla!!!
Longer Follow-Up Confirms Recurrence-Free Survival
Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated
Results From the EORTC 1325-MG/KEYNOTE-054 Trial. Eggermont, Blank, Mandala, et al. J Clin Oncol.
September 18, 2020.
We conducted the phase III double-blind European Organization for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054
trial to evaluate pembrolizumab versus placebo in patients with resected
high-risk stage III melanoma. On the basis of 351 recurrence-free survival
(RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS compared
with placebo. This led to the approval of pembrolizumab adjuvant treatment by
the European Medicines Agency and US Food and Drug Administration. Here, we
report an updated RFS analysis at the 3.05-year median follow-up.
A total of 1,019 patients with complete lymph node
dissection of American Joint Committee on Cancer Staging Manual, stage IIIA (at least one lymph node metastasis greater than 1
mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were
randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514)
or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or
unacceptable toxicity. The two coprimary end points were RFS in the overall
population and in those with programmed death-ligand 1 (PD-L1)-positive tumors.
Pembrolizumab (190 RFS events) compared with placebo (283
RFS events) resulted in prolonged RFS in the overall population (3-year RFS
rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively;) and in the
PD-L1-positive tumor subgroup. The impact of pembrolizumab on RFS was similar
in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF
mutation status.
In resected high-risk stage III melanoma, pembrolizumab
adjuvant therapy provided a sustained and clinically meaningful improvement in
RFS at 3-year median follow-up. This improvement was consistent across
subgroups.
Again. Good. Enough with placebo!!!!
There is also an update on the CheckMate 238 trial. Here are my prior posts on that study as it progressed from 2017 and 2018 - Reports on CheckMate 238 Now, this:
Adjuvant nivolumab versus ipilimumab in resected stage
IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a
multicentre, double-blind, randomised, controlled, phase 3 trial. Ascierto, Del Vecchio, Mandala, et al. Lancet Oncol.
September 18, 2020.
Previously, findings from CheckMate 238, a double-blind,
phase 3 adjuvant trial in patients with resected stage IIIB-C or stage IV
melanoma, showed significant improvements in recurrence-free survival and
distant metastasis-free survival with nivolumab versus ipilimumab. This report
provides updated 4-year efficacy, initial overall survival, and late-emergent
safety results.
This multicentre, double-blind, randomised, controlled,
phase 3 trial was done in 130 academic centres, community hospitals, and cancer
centres across 25 countries. Patients aged 15 years or older with resected
stage IIIB-C or IV melanoma and an Eastern Cooperative Oncology Group
performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab
or ipilimumab via an interactive voice response system and stratified according
to disease stage and baseline PD-L1 status of tumour cells. Patients received
intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg
every 3 weeks for four doses, and then every 12 weeks until 1 year of
treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent.
The primary endpoint was recurrence-free survival by investigator assessment,
and overall survival was a key secondary endpoint. Efficacy analyses were done
in the intention-to-treat population (all randomly assigned patients). All
patients who received at least one dose of study treatment were included in the
safety analysis. The results presented in this report reflect the 4-year update
of the ongoing study with a database lock date of Jan 30, 2020. This study is
registered with ClinicalTrials.gov, NCT02388906.
Between March 30 and Nov 30, 2015, 906 patients were
assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1
months with nivolumab and 50·9 months with ipilimumab; 4-year recurrence-free
survival was 51·7% in the nivolumab group and 41·2% in the ipilimumab group.
With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453
patients in the ipilimumab group) of 302 anticipated deaths, 4-year overall
survival was 77·9% with nivolumab and 76·6% with ipilimumab. Late-emergent
grade 3-4 treatment-related adverse events were reported in three (1%) of 452
and seven (2%) of 453 patients. The most common late-emergent treatment-related
grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and
pneumonitis (one patient each) in the nivolumab group, and colitis (two
patients) in the ipilimumab group. Two previously reported treatment-related
deaths in the ipilimumab group were attributed to study drug toxicity (marrow
aplasia in one patient and colitis in one patient); no further
treatment-related deaths were reported.
At a minimum of 4 years' follow-up, nivolumab
demonstrated sustained recurrence-free survival benefit versus ipilimumab in
resected stage IIIB-C or IV melanoma indicating a long-term treatment benefit
with nivolumab. With fewer deaths than anticipated, overall survival was
similar in both groups. Nivolumab remains an efficacious adjuvant treatment for
patients with resected high-risk melanoma, with a safety profile that is more
tolerable than that of ipilimumab.
So, there you go. ALL of these adjuvant therapies provided Stage III/IV melanoma patients whose obvious disease was removed via surgery or radiation better results - no matter if they were treated with ipi, nivo, pembro or the dabrafinib/trametinib combo - than when they were left untreated. Per these reports, here's how things panned out ~
Dabrafinib/trametinib - at 5 years, stage III melanoma patients alive without relapse was 52% with treatment vs 36% with placebo.
Pembrolizumab (Keytruda) - at 3 years, Stage III melanoma patients with recurrence free survival was 63.7% when treated with pembro, vs 44.1% for placebo.
Ipilimumab (Yervoy) - at 4 years, in Stage III and Stage IV melanoma patients, 4 year recurrence free survival was 41.2%. 4 year overall survival was 76.6%.
Nivolumab (Opdivo) - at 4 years, in Stage III and Stage IV melanoma patients, 4 year recurrence free survival was 51.7%. 4 year overall survival was 77.9%.
My thoughts:
The fact that Stage IV patients were included in the study looking at adjuvant ipi and nivo (CheckMate 238 trial) is HUGE!!!!!! It makes comparison to the studies using pembro and the dabrafinib/trametinib combo as adjuvant in Stage III peeps ONLY, difficult to say the least. I would really like to see an adjuvant study in Stage III melanoma patients where Keytruda and Opdivo are compared head to head, using the exact same result parameters and time frames. I doubt there would be any significant difference in results as that has already been found to be the case when those agents are used in treatment of Stage IV melanoma patients - but still. And finally, while the numbers for adjuvant ipi weren't that bad, and certainly much better than placebo, the side effects were greater - so I don't find ipi as a single agent a good choice for adjuvant therapy given the other options.
For what it's worth and with great appreciation to all the ratties ~ les
P.S. FYI - time frames of follow-up matter. As time goes on, more peeps have a chance to progress. So data at three years may be better than outcomes reported at five years.
For instance in this article: 2017 - Nivo better than ipi as adjuvant The data (drawn from Stage III AND Stage IV melanoma patients who took the drugs as adjuvant) demonstrates this:
That is why it is important to compare apples to apples in all aspects. c
Always find my best information right here. Again, thank you ever so much!
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