I have kicked and screamed about the need for adjuvant treatment for so many years (especially the more effective anti-PD-1 products vs ipi) that it was almost unbelievable when they were finally FDA approved for adjuvant use in 2017 (Opdivo) and 2019 (Keytruda). Sadly, recent trial results for the ipi/nivo combo as adjuvant did not prove more effective - providing instead only a greater side effect profile. Here's a history of adjuvant care in melanoma - ADJUVANT therapy for melanoma!!!!!!!!!!!!!! State of the science.... At this point, targeted therapy in the form of BRAF/MEKi combo's, for BRAF positive patients, and NEO-adjuvant treatments are also available for melanoma patients in need of such care. Here are zillions of adjuvant related reports - Adjuvant care in melanoma
Now, there are these (my comments in red as ever):
Adjuvant Therapy is Effective for Melanoma Patients
with a Positive Sentinel Lymph Node Biopsy Who Forego Completion
Lymphadenectomy. Farrow, Raman,
Williams, et al. Ann Surg Oncol, 2020
Dec 27.
Background: Multiple adjuvant therapies for melanoma have
been approved since 2015 based on randomized trials demonstrating improvements
in recurrence-free survival (RFS) with adjuvant therapy after surgical
resection of high-risk disease. Inclusion criteria for these trials required
performance of a completion lymph node dissection (CLND) for positive sentinel
lymph node (pSLN) disease.
Objective: We aimed to describe current practice for
adjuvant therapies in patients with pSLN without CLND (active surveillance
[AS]), and to evaluate recurrence in these patients.
Methods: Melanoma patients with pSLN between 2016 and 2019
were identified at two institutions. Demographic information, disease and
treatment characteristics, and recurrence details were reviewed
retrospectively. Patients were stratified by recurrence and patient-,
treatment- and tumor-related characteristics were compared using Fisher's exact
test and t test for categorical and continuous variables, respectively.
Results: Overall, 245 SLN biopsies were performed, of which
36 (14.7%) were pSLN. Of 36 pSLN, 4 underwent CLND and 32 underwent AS, of whom
22 (68.8%) received adjuvant therapy with the anti-programmed death-1 (PD1)
inhibitor nivolumab (16/22), anti-cytotoxic T-lymphocyte-associated protein 4
(CTLA-4) inhibitor ipilimumab (3/22), or BRAF/MEK inhibitors (3/22). At a
median follow up of 13.3 months, 7/32 (21.9%) patients on AS recurred,
including 4/22 (18.2%) who received adjuvant therapy and 3/10 (30.0%) who did
not. Tumor ulceration was significantly associated with recurrence. While not
significant, acral lentiginous subtype appeared more common among those with
recurrence.
Conclusion: The majority (68.8%) of patients with pSLN
managed without CLND were treated with adjuvant therapy. The 1-year RFS for
patients managed with adjuvant therapy without CLND was 82%, which is similar
to modern adjuvant therapy trials requiring CLND.
Back in the day, including when I was first diagnosed in 2003 and when I recurred in 2007, patients were routinely treated with a complete lymphadenectomy (CLND) of the area around a positive lymph node. I went through it twice, to both axilla. Times have changed and the process of CLND is no longer recommended. In fact, NEO -adjuvant treatment is being studied to see if starting treatment with the positive node in place provides better results and the data is looking positive. In this report, researchers were looking for differences between melanoma peeps who had a complete lymphadenectomy and those who simply had the positive node removed and started adjuvant treatment. Of 245 sentinel node biopsies they examined - 36 were positive. Of those, 4 patients had CLND and 32 had only the positive node removed. 22 were given adjuvant treatment - 16 were treated with nivo, 3 with ipi, and 3 with BRAF/MEK. At 13.3 months of follow-up - 7 of the 32 patients had recurred - 4 of whom had been treated with adjuvant therapy (abstract does not note which) and 3 had not. Tumor ulceration was significantly associated with recurrence (which is not news). Overall, the patients who had adjuvant treatment after a positive node, but NO CLND had a recurrence free survival rate of 82% which is similar to patients who were given a CLND and adjuvant therapy. Again, this is no longer news, rather confirmation of what we have understood for some years now.
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.
2020 Nov.
Purpose: We conducted the phase III double-blind European
Organisation 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.
Patients and methods: 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.
Results: 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). The impact of pembrolizumab on RFS was similar in subgroups, in
particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status.
Conclusion: 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
At three years follow up, Stage III patients of all stripes did better after treatment with Pembro than those treated with placebo - demonstrating a recurrence free survival rate of 63.7% for those treated with pembro vs 44.1% for those given placebo. YEP.
Adjuvant Therapy Failure Patterns in the Modern Era of Melanoma Management. Rauwerdink, Molina, Tompers, et al. Ann Surg Oncol. 2020 Dec.
Background: The management of patients with resected stage 3
melanoma has changed significantly due to adoption of the Multicenter Selective
Lymphadenectomy Trial (MSLT)-2 guidelines and to the survival benefit of
adjuvant anti-PD-1 immunotherapy and BRAF/MEK-inhibitor (BRAF/MEKi) therapy.
Data are scarce regarding recurrence patterns, adjuvant therapy responses, and
therapy-associated adverse events (AEs) in the modern era.
Methods: This single-institution, retrospective study
analyzed surgically resected stage 3 and oligometastatic stage 4 patients who
received anti-PD-1, BRAF/MEKi, or surgery with active surveillance only. The
primary end point of the study was recurrence-free survival (RFS). The
secondary end points were the location and clinical characteristics of
recurrence and therapy-associated AEs.
Results: From a cohort of 137 patients, the study enrolled
102 patients treated with adjuvant anti-PD-1 (n = 46), adjuvant BRAF/MEKi (n =
3), or surgery alone (n = 26). During a mean follow-up period of 17 months, 20%
of the ani-PD-1 patients, 13% of the BRAF/MEKi patients, and 42% of the
surgery-only patients experienced recurrence. Log-rank testing showed a
significantly longer RFS for the patients treated with anti-PD-1 [15.3 months;
interquartile range (IQR), 8.2-23.2 months] or BRAF/MEKi (17.9
months; IQR, 12.5-23 months) than for those treated with surgery alone
(11.9 months; IQR, 7.0-17.6 months). In the anti-PD-1 group, AEs occurred less
frequently than in the BRAF/MEKi group (54% vs 80%).
Conclusions: Adjuvant anti-PD-1 and BRAF/MEKi were
associated with significantly improved RFS for the patients with resected stage
3 or 4 melanoma. The BRAF/MEKi group had significantly more AEs than the
anti-PD-1 group. This is the first study to characterize real-world recurrence
in the modern era of adjuvant therapy for melanoma.
This study looked at 102 resected Stage III and Stage IV patients. (Stage III patients whose positive node was removed as well as Stage IV like me when I entered my Phase 1 Nivo trial in 2010, whose metastatic disease had been removed.) 46 were given adjuvant anti-PD-1. 3 were given BRAF/MEKi. 26 had surgery alone. At 17 months 20% of those treated with anti-PD-1, 13% treated with targeted therapy, and 42% of the surgery-only patients had recurred. Recurrence free survival lasted an average of15 months for anti-PD-1 patients, 18 months for the BRAF/Meki group, and only 12 months for those given surgery alone. {While this type of data analysis of outcomes of adjuvant therapy is much needed - TAKE THESE NUMBERS WITH A HUGE GRAIN OF SALT!!!!! THE 46 patients treated with anti-PD-1 and 26 given surgery only -is barely sufficient to make valid statistical analysis possible; the THREE treated with BRAF/MEKi does NOT!!!!!!!!!!!!!!!!!!!!}
The data presented in the reports included in this October 2020 post New follow-up data confirms effectiveness for targeted and immunotherapy as adjuvant in melanoma patients!!! is much better! To whit ~
From 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.
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. At 5 years, the percentage of patients who were alive without relapse was 52% with dabrafenib plus trametinib and 36% with placebo.
From 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.
1,019 patients with complete lymph node dissection ofcutaneous 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. 3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively.
From 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.
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.
FYI - Time frames of follow-up matter. As time goes on, more peeps have a chance to progress. So data at three years is often 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
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