Current melanoma treatment options are nothing short of a miracle to those of us who survived the Melanoma Dark Ages when there were literally NO effective treatments available. Still, melanoma treatment remains far from clear or easy. Should one who is BRAF positive choose immunotherapy or targeted therapy? Does one opt for anti-PD-1 as a single agent or combined with anti-CTLA-4 (ipi)? [Noting that the combo is not yet approved for Stage III patients.] And if those puzzlers are not enough, what do you do if you respond to anti-PD-1 initially, but then progress either while still on it or after having been on it? Research has been trying to grapple with these questions ~
2018: Melanoma patients treated beyond progression with anti-PD-1 - with the conclusion that: "Treatment beyond progression with anti-PD-1 antibody therapy might be appropriate for selected patients with unresectable or metastatic melanoma, identified by specific criteria at the time of progression, based on the potential for late responses in the setting of the known toxicity profile."
2018: anti-PD-1 after progression - In this report, after progression on stopping anti-PD-1 the authors conclude: "Our data suggest that anti-PD(L)1 therapy should be resumed if progression occurs after a planned anti-PD(L)1 interruption. Further prospective studies are needed to confirm these results. "
and I note: "Small numbers here and not all are melanoma patients. But, some responses on the re-do."
A bit of a review in 2019: Anti-PD-1 results in melanoma patients: outcomes plus responses to retreatment where the new data presented ended up with mixed and unclear results on retreatment.
This post in 2020: Response after discontinuation of anti-PD-1 in melanoma patients whether due to disease progression, side effects or choice - presents articles that try to address what happens to patients who stop anti-PD-1 therapy.
So, as you can see, many patients and their docs are unclear as to what path is best if a patient progresses or recurs while on or after anti-PD-1 therapy.
Now, there's this:
Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy. Owen, Shoushtari, Chauhan, et al. Ann Oncol. 2020 May 6.
BACKGROUND:
Anti-PD-1 antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25-30% of patients recur within one year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy.
PATIENTS AND METHODS:
Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately.
RESULTS:
Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n=136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months, and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 evaluable patients (24%) responded to ipilimumab (alone or in combination with PD1), and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, 2/5 (40%) responded to PD1 monotherapy, 2/5 (40%) responded to ipilimumab-based therapy, and 9/10 (90%) responded to BRAF/MEK inhibitors.
CONCLUSIONS:
Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.
These researchers looked at 850 Stage III and IV melanoma patients who had their disease removed and were treated with anti-PD-1. 17% (136 patients) recurred. Average time to recurrence was about 5 months. 76% of those patients (104) recurred while they were still taking anti-PD-1 after about 3 months. 24% of that same subgroup (32 patients) recurred in about 12 months after coming off anti-PD-1. 89 patients were given systemic therapy. Of those who recurred while ON anti-PD-1 ~ none responded to anti-PD-1 as a single agent, 24% responded to ipi alone or in combination with anti-PD-1, and 78% responded to targeted therapy. Of those who recurred AFTER anti-PD-1 ~ 40% responded to retreatment with anti-PD-1, 40% responded to ipi, and 90% responded to targeted therapy. Therefore, their conclusion is as noted above.
There is also this:
Ipilimumab (IPI) alone or in combination with anti-PD-1 ((_( + PD1) in patients with metastatic melanoma (MM) resistant to PD1. Da Silva, Ahmed, Lo, et al. ASCO Meeting Library, 2020.
PD1 induces long-term responses in approximately 30% of MM pts, however 2/3 are resistant (innate or acquired) and will require further treatment. A subset of these pts will benefit from IPI or IPI+PD1, but these pts are yet to be identified. We sought to determine; i) response rate (RR) and survival to IPI+/-PD1 after PD1 progression, and ii) clinical predictors of response and survival to IPI+/-PD1.
MM pts resistant to PD1 and then treated with IPI+/-PD1 were studied.
Of 330 MM pts resistant to PD1 (median time to prog 2.9 months [0.5 – 42.3], 12% adjuvant, 88% metastatic; 70% innate, 30% acquired), 161 (49%) had subsequent IPI and 169 (51%) had IPI+PD1. Characteristics at start of IPI+/-PD1 were similar in IPI vs IPI+PD1 groups (stage M1D 27% vs 34%; elevated LDH 38% vs 40%), except IPI group had more ECOG greater than/= to 1 (60% vs 34%) and less BRAF mutation (mut) (21% vs 37%). Median follow-up from start of IPI+/-PD1 was 22.3 months (19.8 - 25.8); RR was 22%, higher in IPI+PD1 (31%) vs IPI (12%). PFS and OS at 1 year were 20% and 48%, respectively; better with IPI+PD1 (27%/57%) vs IPI (13%/38%). PD1 setting (adjuvant/metastatic) and response did not impact response to IPI+/-PD1. Most pts progressing on adjuvant PD1 had IPI+PD1 (88%) and RR was 33%. Neither the interval between PD1 and IPI+/-PD1 nor use of other drugs affected response to IPI+/-PD1. RR was similar in BRAF WT (23%) vs BRAF mut (RR 21%) pts. In BRAF WT pts, RR was higher with IPI+PD1 vs IPI (38% vs 9%), while RR was similar with IPI (24%) or IPI+PD1 (19%) in BRAF mut pts. One third of BRAF mut pts had BRAF inhibitors (BRAFi) prior to IPI+/-PD1 and lower RR (13%) vs those without BRAFi (RR = 25%). High grade (greater than/= to G3) toxicity (tox) was similar with IPI+PD1 (30%) or IPI (34%), and was not associated with response. Stage III/M1A/M1B, normal LDH and treatment with IPI+PD1 were the best predictors of response. These factors, in addition to sex (male), ECOG PS = 0, BRAF mut, progressed/recurred greater than 3 months on PD1, and absence of bone mets were the best predictors of longer OS.
In pts resistant to PD1, IPI+PD1 has higher RR, longer survival, yet similar high grade tox than IPI alone. Predictive models of response & survival will help select pts for IPI+/-PD1 after progressing on PD1.
This study looked at patients who did not attain long term durable response to initial anti-PD-1 therapy - about 70% of patients. They followed 330 melanoma patients who had progressed on or after anti-PD-1 therapy and were then treated with either ipi alone or ipi combined with anti-PD-1. Overall, patients retreated or changed to the ipi/anti-PD-1 combo had higher response rates and longer survival.
For what it's worth. - c
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