What to do, when what was supposed to work does not? A heart rending question for anyone always! Sadly, in melanoma, there are still no clear answers. Clinical trials are an option. As always, I advocate searching this site: ClinicalTrials.gov From there you can enter your disease and stage, as well as click on the box for active/recruiting trials. Once your list pops up, when you click on each trial, you can look through the drugs to be used and the inclusion/exclusion requirements. At the bottom, you will find a list of locations in which the trial is offered and usually, contact information for the trial coordinator. MY EXHORTATION is this: If you are remotely interested in a trial, even if you think you may not be allowed or even desire participation in, CALL!!!!! Call the facility, ask for info on the trial. You never know what options you may attain from there!
Here are just a few of the current treatment options via trials for melanoma patients with advanced disease:
LOTS of things paired with immunotherapy!!!!!
NKTR-214 - which I have reported on here: NKTR- 214 (bempegaldesleukin) with Opdivo
Many of the current offerings being paired with immunotherapy are as yet an alphabet soup, much like Nivolumab - first MDX-1106, then BMS-936558, then nivolumab and now Opdivo - not sure the names are any better!!! - was in my phase 1 trial back in 2010. Here are just a few: CMP-001. BGB324. APX005M. APG-115. HBI-8000. V937. SX-682. AV-MEL-1. Anti-VEGF. NOVO TTF-200A. IL6 (Tocilizumab). Azacitidine. High dose IL-2. Olaparib. Denosumab. Something I've been reporting on since 2014 - propranolol.
There's radiation with everything. There is TBX-3400 on its own. Fecal transplants - more on that here. Tazemetostat with BRAF/MEK inhibitors. And much more. I am not touting the feasibility (or not) of any of these, but they are available for your consideration.
Anti-LAG-3 is a promising new/additional therapy. You can check out posts here: Anti-LAG-3
I have posted on response rates and outcomes of advanced melanoma peeps as well as results when immunotherapy is followed by immunotherapy as well as targeted therapy after immunotherapy. Here are a couple posts with links within:
From 2020: Five year survival reports in melanoma after various targeted and immunotherapies
After progression on anti-PD1 / anti-PDL1 treatment of melanoma
There is this report: Advanced Melanoma - A smattering of 2020 literature for Stage IV peeps which includes one report on using antiangiogenic drugs as salvage therapy when other treatments have not been successful. Which brings us here - old school chemo options, alone or combined with immunotherapy, to consider:
Potential therapeutic effect of low-dose paclitaxel in
melanoma patients resistant to immune checkpoint blockade: A pilot study. Gebhardt, Simon, Weber, et al. Cell Immunol. Feb 2021.
The low dose application of chemotherapeutic agents such as
paclitaxel was previously shown to initiate anti-tumor activity by neutralizing
myeloid-derived suppressor cells (MDSCs) in melanoma mouse models. Here, we
investigated immunomodulating effects of low-dose paclitaxel in 9 metastatic
melanoma patients resistant to prior treatments. Three patients showed response
to therapy (two partial responses and one stable disease). In responding
patients, paclitaxel decreased the frequency and immunosuppressive pattern of
MDSCs in the peripheral blood and skin metastases. Furthermore, paclitaxel
modulated levels of inflammatory mediators in the serum. In addition,
responders displayed enhanced frequencies of tumor-infiltrating CD8+ T cells
and their activity indicated by the upregulation of CD25 and TCR ζ-chain
expression. Our study suggests that low-dose paclitaxel treatment could improve
clinical outcome of some advanced melanoma patients by enhancing anti-tumor
immunity and might be proposed for combined melanoma immunotherapy.
Chemotherapy combined with antiangiogenic drugs as
salvage therapy in advanced melanoma patients progressing on PD-1
immunotherapy. Wang, Xu, Si, et
al. Transl Oncol. Jan 2021.
Background: This study aimed to evaluate the effect of
salvage therapy with nab-paclitaxel (nab-p) or temozolomide (TMZ) combined with
antiangiogenic drugs in programmed death 1 (PD-1) inhibitor-resistant patients
with unresectable metastatic melanoma.
Methods: We conducted a retrospective review of 69
metastatic melanoma patients who received nab-p or TMZ combined with antiangiogenic
drugs after developing PD-1 inhibitor resistance and were treated at the
Beijing Cancer Hospital between 2016 and 2019. The disease control rate (c-DCR)
and progression-free survival (c-PFS) of salvage CA (chemotherapy combined with
antiangiogenic drugs) regimens were investigated. Univariate and multivariate
analyses were performed to evaluate the clinical pathological factors affecting
the outcomes. Then, a nomogram was formulated to predict the probability of
3-month and 6-month c-PFS based on the multivariate analysis results.
Results: The c-DCR was 63.8%, and the median c-PFS was 3.0
months. In the univariate analysis, factors associated with the c-DCR were
included the melanoma subtype, baseline platelet-to-lymphocyte ratio (PLR) and
best response status to PD-1 inhibitors. Factors influencing c-PFS included
age, baseline lactic dehydrogenase, PLR, neutrophil-to-lymphocyte ratio (NLR),
PFS duration of anti-PD-1 therapy (p-PFS), and the best response and
progression pattern of PD-1 inhibitors. In the multivariate analysis, age
<65 years, heterogeneous progression pattern and baseline PLR<200 were
significantly associated with improved c-PFS. The concordance index (C-index)
of the nomogram was equal to 0.65.
Conclusions: CA regimens demonstrated promising effects in
PD-1 inhibitor-resistant patients. The nomogram could be a valuable predictive
module for salvage therapy choice in PD-1 inhibitor-resistant patients.
In plain English, these researchers attempted to created an algorithm to predict what amount of time the chemo cocktail would give a person. It is not clear how accurate their predictions were.
From ASCO, there is this:
Lenvatinib (len) plus pembrolizumab (pembro) for patients (pts) with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: Updated findings of LEAP-004. Arance, Cruz-Merino, Petrella, et al. ASCO 2021.
Background: Initial results of the open-label, single-arm, phase 2 LEAP-004 study (NCT03776136) showed that len and pembro in combination had promising efficacy and manageable safety in pts with unresectable stage III-IV melanoma and confirmed PD on a PD-(L)1 inhibitor given alone or in combination. ORR was 21.4% with a 6.3-mo median DOR; ORR was 31.0% in patients with PD on prior anti–PD-1 + anti–CTLA-4. We present updated data from LEAP-004 and additional ORR subgroup analyses.
Methods: Eligible pts with PD confirmed per iRECIST within 12 wk of the last dose of a PD-(L)1 inhibitor given alone or with anti–CTLA-4 or other therapies for greater than/= to 2 doses received len 20 mg/d once daily plus less than/= to 35 doses of pembro 200 mg Q3W until PD or unacceptable toxicity. Primary end point is ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are PFS and DOR per RECIST v1.1 by BICR, OS, and safety. ORR was calculated for pts with PD on prior anti–PD-1 + anti–CTLA-4, pts whose only prior anti–PD-(L)1 was in the adjuvant setting, pts with primary resistance (ie, best response of SD or PD to prior anti–PD-(L)1 in the advanced setting) and pts with secondary resistance (ie, PD following best response of CR or PR on prior anti–PD-(L)1 in the advanced setting).
Results: 103 pts were enrolled. Median age was 63 y, 68.0% of pts had stage M1c/M1d disease, 55.3% had LDH greater than ULN, 58.3% received greater than or = to 2 prior treatments, 94.2% received therapy for advanced disease, and 32.0% received BRAF ± MEK inhibition. With median study follow-up of 15.3 mo (range 12.1-19.0), 17.5% of pts were still receiving study drug. ORR by BICR remained 21.4%, although the number of CRs increased from 2 to 3. DCR was 66.0%. Median DOR increased to 8.2 mo, and the KM estimate of DOR greater than/= to 9 mo was 37.2%. ORR was 33.3% in pts with PD on prior anti–PD-1 + anti–CTLA-4 (n = 30), 18.2% in pts whose only prior anti–PD-1/L1 was in the adjuvant setting (n = 11), 22.6% in pts with primary resistance (n = 62), and 22.7% in pts with secondary resistance (n = 22). Median PFS and OS in the total population were 4.2 mo (3.8-7.1) and 14.0 mo; 12-mo PFS and OS estimates were 17.8% and 54.5%. Incidence of treatment-related AEs was as follows: 96.1% any grade, 45.6% grade 3-4, 1.0% grade 5 (decreased platelet count), 7.8% led to discontinuation of len and/or pembro, and 56.3% led to len dose reduction.
Conclusions: The combination of len and pembro continues to show clinically meaningful, durable responses in pts with advanced MEL with confirmed progression on a prior PD-(L)1 inhibitor, including those with PD on anti–PD-1 + anti–CTLA-4 therapy, and regardless of primary or secondary resistance to prior anti–PD-(L)1 therapy. The safety profile was consistent with prior studies of len + pembro. These data support len + pembro as a potential regimen for this population of high unmet need.
Still hoping for therapies that rid disease from ALL melanoma peeps! Hang tough, dear ones. Hang tough! - c
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