Yeah. Most of this jazz, is NOT news.
I have been yelling about NLR and its relationship to response in melanoma patients FOREVER!!! Here are only a million prior reports: Better melanoma outcomes with a lower NLR, neutrophil-to-lymphocyte ratio! (Again...) Now, this:
Association of baseline
neutrophil-to-lymphocyte ratio (NLR) with response and survival in advanced
melanoma (MEL) receiving PD-1 inhibitors. 2019 ASCO. Hemadri, Lin, Lin, et al.
Background: Inflammation
is an adverse prognostic factor in cancer. Neutrophil-to-lymphocyte ratio (NLR)
is an easily derived biomarker of systemic inflammation. Several studies have
demonstrated that elevated NLR is linked with adverse prognosis in patients
(pts) receiving immunotherapy including PD-1 inhibitors. To evaluate the
prognostic utility of NLR, we performed a retrospective evaluation of NLR and
other covariates in stage IV cutaneous MEL. Methods: Stage IV cutaneous MEL pts who received anti PD-1
therapy at the University of Pittsburgh between 2014-2018 were included in this
analysis. PD-1 blockade was continued until progression or intolerable
toxicity. Tumor assessment was performed at baseline and every 12 weeks and
response classified per RECIST v1.1. Clinical and demographic data were
obtained. Baseline NLR was defined based on values at the first treatment date.
Descriptive statistics were created for all covariates. Kaplan Meier and Cox
proportional hazard regression were performed to assess how variables related
to response (ORR), overall survival (OS) and progression free survival (PFS)
measured in months (mos). Results: 172
pts with advanced MEL were evaluated. Elevated NLR was associated with poorer
PFS and OS and ORR at all cutoffs (NLR greater than/= to 2 to NLR greater than/= to 5) with NLR greater than/= to 5 having the
greatest discriminative value. ORR steadily declined with increasing NLR: NLR greater than/= to 1
(ORR 64%), NLR greater than/ = to 2 (ORR 61%), NLR greater than/= to 3 (ORR 52%), NLR greater than/= to 4 (ORR 43%), NLR greater than/ = to 5 (ORR 43%).
Elevated NLR was associated with poorer PFS (median 21.5 mos
vs. 5.2 mos) and OS (median 35.4 mos vs. 10.6 mos).
In a multivariate model, elevated NLR was independently
associated with poorer OS/PFS separate from ulceration, performance status and
elevated LDH. There was no evidence of an age-related increase or decrease in
NLR. Conclusions: Baseline
NLR was independently associated with response, PFS and OS in the largest
retrospective series of advanced MEL pts treated with PD-1 blockade. NLR
independent of other factors predicted poorer PFS and OS at NLR cutoffs (NLR greater than/= to 3
to NLR greater than/= to 5), although NLR greater than/+ to 5 segregated pts best. NLR is an inexpensive and easily
obtained real-world biomarker that has a high value in predicting outcomes to
PD-1 blockade.
Once again, elevated NLR was associated with worse outcomes across the board, including PFS, OS, and ORR - in melanoma patients treated with immunotherapy - even when separated from ulceration, patient status, and elevated LDH. This is a cheap and easy test that might aid patients and docs in their selection of treatment options!
When dealing with brain mets, we have learned that when systemic therapy (targeted or immunotherapy) is combined with radiation (SRS) the response is better than with either treatment option alone. Here are a zillion reports: Radiation combined with systemic therapy in melanoma treatment - 2015 forward Now, this:
First-line stereotactic radiosurgery combined
with systemic targeted and immune checkpoint inhibitor therapy in melanoma
patients with newly diagnosed brain metastases. 2019 ASCO. Heumann, Wu, Ye, ..., Weber, Pavlick, et al.
Background: Of solid
tumors, melanoma has the highest propensity for central nervous system spread
with historic median survivals of 5-8 months following brain metastasis
diagnosis. We evaluated the impact of systemic BRAF targeted and immune
checkpoint inhibitor (ICI) therapies on survival outcomes in patients receiving
stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM) and
assessed patient treatment burden associated with prolonged survival. Methods: We retrospectively reviewed
the demographics, disease characteristics, therapeutic regimens, overall
survival, and first-year cumulative incidence of comorbid disease for patients
with de novo MBM treated between 2013 and 2017 at a major melanoma referral
center. Results: Among 123
newly diagnosed MBM patients: 65% were male, 24% were
50 years old or less, 50% were BRAF mutated, 63%
had multiple intracranial lesions at diagnosis. Locally, 73%
received SRS as first-line treatment.Systemically, 73% received ICI, 46%
received BRAF targeted therapy, and 12% received neither. With median follow up
of 11 months (mo), total cohort
median OS was 13.2 mo, 20.5 mo for BRAF mutated patients, 10.8 mo for BRAF
wild-type patients. Median OS for first-line SRS was 31.0 mo (47% 3-year OS)
when combined with both ICI and BRAF targeted therapy, 17.5 mo (31% 3-year OS)
when combined with ICI monotherapy, and 6.1 mo (22% 3-yr OS) with neither
systemic therapy. SRS and BRAF targeted therapy were associated with improved
OS. BRAF status, ICI therapy, intratumoral hemorrhage were not significant
prognosticators for OS.At one-year follow-up, comorbid conditions with the
greatest cumulative incidence were fatigue, nausea, intracranial hemorrhage,
deep vein thrombosis, major depressive disorder, and pneumonia. Patients
averaged one inpatient visit every 4.5 mo (1 week average length of stay), and
2 advanced imaging studies (MR/CT/PET-CT) per month following MBM
diagnosis. Conclusions: In
one of the largest reported MBM series, survival has improved markedly for
patients receiving first-line brain radiosurgery combined with BRAF targeted
therapies and immunotherapies. Simultaneously, longer life expectancy comes
with increasing incidences of comorbid conditions reflecting an evolving
complexity of and need for coordination of care for patients with MBM.
Wait for it... Folks with melanoma brain mets did better when they were treated with targeted therapy or immunotherapy combined with radiotherapy, than with either of the treatments as single agents!
COX inhibitors, your basic NSAID's ~ think aspirin or advil ~ have long been a topic of discussion as they relate to responses from immunotherapy. In this post from 2015, An aspirin a day...keeps melanoma at bay....and makes immunotherapy work better!!!!, I noted, "...here's the deal: To back up a step - NSAIDs block an enzyme, cyclooxygenase (also called: COX1 and COX2). Blocking those enzymes, blocks the production of prostaglandins. Soooo..... These researchers used genetically modified mice to research the role of prostaglandins in blocking immune rejection of tumors. Aspirin and similar NSAIDs stop the production of prostaglandins, thereby allowing immune cells to kill tumors more easily and enhancing the checkpoint inhibitors like anti-PD1 (nivo/opdivo and pembro/keytruda), anti-PDL1, and anti-CTLA4 (ipililmumab). Researchers note:
Then there was some back and forth in this composite of many posts and articles in 2018: Aspirin, NSAID's, and melanoma Now, there's this:
Wait for it... Folks with melanoma brain mets did better when they were treated with targeted therapy or immunotherapy combined with radiotherapy, than with either of the treatments as single agents!
COX inhibitors, your basic NSAID's ~ think aspirin or advil ~ have long been a topic of discussion as they relate to responses from immunotherapy. In this post from 2015, An aspirin a day...keeps melanoma at bay....and makes immunotherapy work better!!!!, I noted, "...here's the deal: To back up a step - NSAIDs block an enzyme, cyclooxygenase (also called: COX1 and COX2). Blocking those enzymes, blocks the production of prostaglandins. Soooo..... These researchers used genetically modified mice to research the role of prostaglandins in blocking immune rejection of tumors. Aspirin and similar NSAIDs stop the production of prostaglandins, thereby allowing immune cells to kill tumors more easily and enhancing the checkpoint inhibitors like anti-PD1 (nivo/opdivo and pembro/keytruda), anti-PDL1, and anti-CTLA4 (ipililmumab). Researchers note:
- Prostaglandins in tumors interferes with immune cell function.
- Blocking cyclooxygenase in tumors restores immune cell function.
- The cyclooxygenase blockers (NSAIDs) increase the action of checkpoint inhibitors.
- This mechanism is shared by mouse and human tumor systems.
Then there was some back and forth in this composite of many posts and articles in 2018: Aspirin, NSAID's, and melanoma Now, there's this:
Evaluating the role of the COX2/PGE2 pathway in anti-melanoma
immunity. 2019 ASCO. Ferreira, Krybaeva, et al.
Background: Checkpoint inhibitors such as anti-PD1
(aPD1) have revolutionized treatment of metastatic melanoma. However, a large
subset of patients receiving such treatment fails to respond to aPD1
monotherapy due to mechanisms such as PD-L1 upregulation within the tumor and T
cell exhaustion in the tumor microenvironment. The PGE2/COX2 signaling pathway
is one of the pathways implicated in T cell exhaustion and PD1/PD-L1
upregulation and thus represents an attractive pharmacologic target to enhance
effects of aPD1 therapy due to the availability and safety of inhibitors such
as aspirin or NSAIDs. There is evidence that PGE2/COX2 pathway inhibitors act
synergistically with aPD1 therapy in murine melanoma and breast cancer models.
Here we aimed to further characterize this synergism using the YUMMER (Yale
University Mouse Melanoma Exposed to Radiation) 1.7 model, an irradiated,
syngeneic cell line originating from BrafV600E; Pten-/-;
and Cdkn2a-/- genetically engineered mouse melanomas.
YUMMER1.7 cells implanted into the flanks of C57BL6/j mice show reproducible
but partial responses to intraperitoneal aPD1 therapy and thus serves as an
ideal platform to study whether concurrent PGE2/COX2 pathway blockade may
result in additive effects to aPD1 therapy. Methods: 6-7
week old male C57BL6/j mice (n = 20) were injected with 500K YUMMER1.7 cells
and treated with aPD1 therapy alone starting on day 7 after tumor implantation
(n = 10) or with aPD1 therapy starting on day 7 in addition to ibuprofen
dissolved in drinking water at a concentration of 1 mg/mL started on the day of
tumor implantation (n = 10). Using an average daily water consumption estimate
of 6 mL/day, this translates to a human equivalent of roughly 1200 mg/day, a
moderate dose of ibuprofen. Tumor growth was monitored and tracked to an
endpoint of 1cm3. Results: Tumor
volume at day 17 significantly differed between the two groups.
Survival curves were significantly different between the two groups (p <
0.0001); all tumors treated with aPD1 alone grew to endpoint by day 32, while
all tumors treated with aPD1 + ibuprofen regressed with 8 out of 10 showing
complete regression by day 32. Conclusions: We have shown that
ibuprofen strongly synergizes with aPD1 therapy in a murine model of melanoma,
complementing existing evidence. This suggests that PGE2/COX2 inhibitors such
as NSAIDs, which are over-the-counter agents with a well-studied safety
profile, may serve as a promising means of enhancing the response to aPD1
therapies such as nivolumab in melanoma patients who initially fail aPD1
monotherapy.
Well, okie dokie then! Not sure just taking anti-PD-1 with an aspirin is going to work for folks who failed anti-PD-1 in the first place, especially since I think it would be a hard task to find a melanoma peep on anti-PD-1 who hasn't had to dip into the NSAID bottle of choice in order to survive the assorted aches and pains that come with that therapy! But what do I know?????
There is beauty still...
... even if we come through the storm looking something like a Dr. Seuss flower! - c
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