Tuesday, July 16, 2019

Pre-operative ultrasound of lymph nodes NO substitute for SLNB in melanoma patients in finding positive nodes and determining stage!!


It would be great if you could just have an ultrasound of the nodal basin near your lesion to determine whether or not there are any positive nodes hiding in there!  However, there's this:

Preoperative Ultrasound Assessment of Regional Lymph Nodes in Melanoma Patients Does not Provide Reliable Nodal Staging: Results from a Large Multicenter Trial.  Thompson, Havdu, Uren, et al. Ann Surg. 2019 Jun 7. 

To assess whether preoperative ultrasound (US) assessment of regional lymph nodes in patients who present with primary cutaneous melanoma provides accurate staging.

It has been suggested that preoperative US could avoid the need for sentinel node (SN) biopsy, but in most single-institution reports, the sensitivity of preoperative US has been low.

Preoperative US data and SNB results were analyzed for patients enrolled at 20 centers participating in the screening phase of the second Multicenter Selective Lymphadenectomy Trial. Excised SNs were histopathologically assessed and considered positive if any melanoma was seen.

SNs were identified and removed from 2859 patients who had preoperative US evaluation. Among those patients, 548 had SN metastases. US was positive (abnormal) in 87 patients (3.0%). Among SN-positive patients, 39 (7.1%) had an abnormal US. When analyzed by lymph node basin, 3302 basins were evaluated, and 38 were true positive (1.2%). By basin, the sensitivity of US was 6.6% and the specificity 98.0%. Median cross-sectional area of all SN metastases was 0.13 mm; in US true-positive nodes, it was 6.8 mm. US sensitivity increased with increasing Breslow thickness of the primary melanoma (0% for less than/= to1 mm thickness, 11.9% for greater than/= to 4 mm thickness). US sensitivity was not significantly greater with higher trial center volume or with pre-US lymphoscintigraphy.

In the MSLT-II screening phase population, SN tumor volume was usually too small to be reliably detected by US. For accurate nodal staging to guide the management of melanoma patients, US is not an effective substitute for SN biopsy.

SO - in this study - because it had been hypothesized that doing an ultrasound of nodes near a melanoma lesion before surgery could identify whether, OR NOT, there was melanoma present in those nodes, indicating a need, OR NOT, for surgery - these researchers looked at the nodes of 2,859 peeps via ultrasound before they underwent sentinel node removal.  Of those 2,859 melanoma patients, 548 had a sentinel node that was positive for melanoma.  Of those 548, only 87 had a positive node identified on their preoperative ultrasound.

Clearly, that's not good enough.  If we were to rely on US to find positive nodes, this study indicates that 461 of these 548 melanoma peeps would still be walking around with:
1) A positive sentinel node that they didn't know they had - period. 
2) A missed opportunity to realize their real status as a Stage III melanoma patient and relinquish their opportunity for viable adjuvant care.
I wish sentinel nodes could be evaluated by a simple procedure like an US.  However, the state of the technology is not there yet.  Maybe someday.  For what it's worth. - c

Wednesday, July 10, 2019

Melanoma patients and the development of additional cancers


Well, hell!  Sorry, Julie.  But, this one's for me and you!!!

Melanoma patients with additional primary cancers: a single-center retrospective analysis.  Dimitriou, Mangana, Curioni-Fontededro, et al.  Oncotarget. 2019 May 21.

Background: Recent progress in the diagnosis and treatment of primary and metastatic cutaneous melanoma (CM) has led to a significant increase in the patients` expectancy of life. The development of additional primary tumors (APT) other than CM represents an important survival issue. Results: Of a total of 1764 CM patients, 80 (4.5%) patients developed APT. For tumors diagnosed after CM, there was a 2.7 fold excess risk for APT compared to the swiss german population. A significantly increased risk was noted for female breast (SIR, 2.46), male larynx (SIR, 76.92), male multiple myeloma (SIR, 11.2), male oesophagus (SIR, 10.8) and thyroid on males (SIR, 58.8) and females (SIR, 38.1). All thyroid cancer cases had a common papillary histological subtype and a high rate of BRAFV600E mutation. Melanoma was the primary cause of death in the vast majority of patients. Methods: We used the cancer registry from the Comprehensive Cancer Center Zurich (CCCZ) and retrospectively analyzed patients with CM and APT between 2008 and 2018. We calculated the risk of APT compared to the Swiss German population using the standardized incidence ratio (SIR). Conclusions: Patients with CM have an increased risk for hematologic and solid APT. Long-term follow-up is indicated.

So, in this review of 1,764 patients with cutaneous melanoma, 80 of them (4.5%) developed additional primary tumors.

If we had to "beat" the odds, Julie, then why couldn't we have been one of Bernie's top 5% wealth mongers rather than part of this cancer co-op??????!!!!!  Bahaha!!!  Oh, well.  Though we don't like, we can deal, right???  Despite our sucky odds, there is beauty...


...still.  Wishing you my best, my friend.  Much love and shalom, les

Friday, July 5, 2019

Cut it out!!! Prolonged overall survival following metastasectomy in Stage IV melanoma



When in doubt - cut it out!!!

Prolonged Overall Survival Following Metastasectomy in Stage IV Melanoma.  Elias, Behbahani, Maddukuri, et al.  J Eur Acad Dermatol Venereol. 2019 May 9. 

Current literature supports mixed conclusions regarding the outcomes of metastatectomy in Stage IV melanoma. The objective of this national study was to determine the associations of non-primary site surgery with overall survival (OS) in Stage IV melanoma.

The National Cancer Database (NCDB) was queried for all Stage IV melanoma cases diagnosed from 2004 to 2015. Cases missing treatment/staging data or undergoing palliative treatment were excluded (remaining n=14,034). Patients were separated into 'metastatectomy' (n=4,214, 30.0%) and 'non-metastatectomy' (n=9,820, 70.0%) cohorts. Survival outcomes were analyzed using Kaplan-Meier and Cox proportional hazards regressions.

On univariate analysis, patients with Stage IV melanoma undergoing metastatectomy (median survival:15.67mo) had greater overall survival compared to those not receiving non-primary surgery (median survival: 7.13 mo) [5-year OS 13.2% vs. 5.6%].

Metastatectomy for Stage IV melanoma is independently associated with improved OS in metastatic cases involving the skin, lung, and visceral organs. 

Here, researchers reviewed records of Stage IV melanoma peeps with tumors in their "skin, lung and visceral organs" recorded in the National Cancer Database from 2004-2015.  Leaving out those who had incomplete records and those on hospice, they found 14,034 cases to examine.  30% of those (4,214) had their tumors surgically removed, 70% (9,820) did not.  Median survival for those who had their melanoma cut out was almost 16 months while those who did not had a median survival of 7 months.  When looking at 5 year survival in these groups, it was 13.2% for those who had surgery vs 5.6% for those who did not.  

Now, to be fair, it is not clear which of these patients were able to attain effective systemic therapy vs those who did not as this time frame covers a period in which current immnotherapies and targeted therapies were and were NOT available.  Still, just like antibiotics and bacterial infections - we have learned that therapies work best with the lowest tumor burden.  Meaning - if you have a localized infection, antibiotics often take care of it easily.  However, if the bacterial growth becomes overwhelming, throwing all the antibiotics in the world at it will not prevent the patient from succumbing to sepsis.  Likewise, we know that when melanoma patients have their tumor removed completely or even debulked, immunotherapy works much better.  That is the entire premise of adjuvant care in melanoma.  But, because melanoma likes to be a completely freaky unpredictable be-atch, we are more recently noting, that "NEO-adjuvant" care, giving treatment before surgery, then having the tumor removed, while continuing the systemic therapy for a period of time after surgery, is showing promise.  We still have a lot to learn about that, with ratties currently leading the way, as researchers hypothesize that by utilizing this approach the immune system is primed (learns to recognize the tumor despite its upcoming removal), the systemic therapy not only shrinks the tumor making surgery less of a big deal, it then "sweeps the area" of microscopic or residual inoperable disease with its use after surgery as we have already proven with basic "adjuvant" care.  We have yet to see exactly how this will all play out in the long run, but I suspect surgery will still remain a very important life saving tool in melanoma care.

Here is a recent report (with additional links within) on neo-adjuvant treatment: BRAF/MEK before surgery as well as after is MUCH better, than just AFTER surgery for melanoma!! Plus trial still recruiting resectable stage III/IV melanoma peeps.

As well as this recent report on Clinical condition of melanoma peeps and associated outcomes when treated with anti-PD-1 vs anti-PD-1 and ipi, which notes:  [When looking at the use of anti-PD-1 alone] size of the largest tumor was independently associated with PFS, OS, and RR, whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not.In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS  and RR but not OS.  Therefore, indicating that total tumor burden (most in patients treated with anti-PD-1 as a single agent and less with the ipi/nivo combo) continues to impact response to immunotherapy in melanoma patients.

Leave it to melanoma to make every decision as complicated as possible - but there is beauty...


...still. ~ c

Wednesday, July 3, 2019

IPI/NIVO - results - in melanoma brain mets and long term follow-up in advanced melanoma


Yes.  I think the results ratties provided have finally gotten it through most researchers heads (though not the heads of all oncologists) that targeted therapy (via the BRAF/MEK combo for BRAF positive melanoma peeps) and immunotherapy WORK IN THE BRAIN!!!!  I have been reporting on this trial CheckMate 204 since 2015.  Now, there's this:

Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204).  2019 ASCO.  Tawbi, Forsyth, Hodi...Hamid...Postow, Pavlick...et al. J Clin Oncol 37, 2019 (suppl; abstr 9501)

Background: We previously reported efficacy and safety of NIVO+IPI in patients (pts) with untreated, asymptomatic, melanoma brain metastases (MBM) from the CheckMate 204 study. Here, we provide the first report of NIVO+IPI in pts with symptomatic MBM, and report updated data in pts with asymptomatic MBM. Methods:In this phase II trial, pts with  greater than/= to 1 measurable, nonirradiated MBM 0.5–3.0 cm were enrolled into two cohorts: (1) those with no neurologic symptoms or steroid Rx (asymptomatic; cohort A); and (2) those with neurologic symptoms, whether or not they were receiving steroid Rx (symptomatic; cohort B). In both cohorts, pts received NIVO 1 mg/kg + IPI 3 mg/kg Q3W × 4, then NIVO 3 mg/kg Q2W until progression or toxicity. The primary endpoint was intracranial clinical benefit rate (CBR; proportion of pts with complete response [CR] + partial response [PR] + stable disease [SD]  greater than/= to 6 mo). As of the clinical cutoff date on May 1, 2018, all treated pts (101 in cohort A and 18 in cohort B) had been followed for ~6 mo or longer. Results: In this updated analysis of cohort A (median follow-up of 20.6 mo), the CBR was 58.4% (Table). In cohort B, pts received a median of 1 NIVO+IPI dose and 2 of 18 pts (11%) received all 4 doses. At a median follow-up of 5.2 months in cohort B, intracranial objective response rate was 16.7% and the CBR was 22.2%. Grade 3/4 adverse events occurred in 54.5% of pts in cohort A and in 55.6% of pts in cohort B (6.9% and 16.7% in the nervous system, respectively), with one death related to treatment in cohort A (immune-related myocarditis). Conclusions: In pts with asymptomatic MBM, our updated results show a high rate of durable intracranial responses, further supporting NIVO+IPI as a first-line treatment in this population. Intracranial antitumor activity was observed with NIVO+IPI in pts with symptomatic MBM, but further study is needed to understand the biologic mechanisms of resistance to immunotherapy and to improve treatments in this challenging population. Clinical trial information: NCT02320058

Intracranial response
Asymptomatic
(Cohort A; n = 101)
Symptomatic
(Cohort B; n = 18)
Best overall response, n (%)


CR
29 (29)
2 (11)
PR
26 (26)
1 (5.6)
SD ≥6 mo
4 (4)
1 (5.6)
CBR, % (95% CI)
58.4 (48.2–68.1)
22.2 (6.4–47.6)

While I am glad to note those responses, you would be hard pressed to convince me to go with ipi/nivo alone...given all we have learned about the positive response systemic therapy COMBINED with radiotherapy provides.  You can read a zillion articles on the combo here:  
Radiation for melanoma

I am not even going to try to note ALL the posts and discussions I have reported regarding the ipi/nivo combo!  We have long known that the 15% response rate to ipi alone and the 40% average response rate to either anti-PD-1 product alone jumps to around 50+% with the ipi/nivo combo.  Just put "ipi/nivo" in the search bar to read the history for yourself.  Now, there's this:

Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma.  2019 ASCO.  Akins, Kirkwood, Wolchok, ..., Postow, ...Sznol.  J Clin Oncol 37, 2019.


Background: We previously reported a 3-year overall survival (OS) rate of 63% with NIVO+IPI concurrent therapy in the initial phase I dose-escalation study for the combination, conducted in patients (pts) with advanced melanoma. Here, we report OS after 5 years of overall study follow-up and assess survival rates after stopping treatment. Methods: Adults with previously treated or untreated unresectable stage III or IV melanoma, and ECOG performance status of 0 or 1, received NIVO + IPI Q3W × 4 as mg/kg in one of the following cohorts: (1) NIVO 0.3 + IPI 3; (2) NIVO 1 + IPI 3; (2a) NIVO 3 + IPI 1; (3) NIVO 3 + IPI 3; (8) NIVO 1 + IPI 3. Cohorts 1-3 received maintenance with NIVO Q3W × 4, then NIVO + IPI Q12W × 8 at assigned doses; cohort 8 received NIVO Q2W for up to 96 weeks. Patients were followed for the primary endpoint of safety and the secondary endpoints of response and progression-free survival for up to 2.5 years, then for the survival exploratory endpoint for up to an additional 3 years, for a maximum study participation of 5.5 years. Results: At a median follow-up of 43.1 months in all cohorts (N = 94), the 4- and 4.5-year OS rates were both 57%. The 4-year OS rates for pts with normal (n = 58) versus elevated LDH (n = 36) were 62% versus 49%; for pts with wild-type (n = 66) and mutant (n = 24) BRAF tumors, 4-year OS rates were 54% and 61%, respectively. Following the last dose of study drug (for any reason), overall post-treatment 1-, 2-, and 3-year OS rates were 74%, 65%, and 56%, respectively; in pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84%, 75%, and 65%, respectively, and in pts who discontinued for disease progression (n = 30), these were 52%, 34%, and 24%, respectively. Conclusions: This updated analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma. Clinical trial information: NCT01024231

Yep.  "...analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma."  NOW!  Let's make these numbers even better!!!

We are beautiful before, during, and after...


...the storm. ~ c

Monday, July 1, 2019

Old Stuff from the newest ASCO - NLR association with response and survival in advanced melanoma, SRS with targeted or immunotherapy for melanoma brain mets, COX2 inhibitors (NSAID's) and improved response to anti-PD-1 therapy in melanoma


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.   J Clin Oncol 37, 2019 (suppl; abstr 9571)

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.  J Clin Oncol 37, 2019 (suppl; abstr e13577)

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:
  • 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.
My thoughts:  While you can find conflicting reports regarding effects of NSAIDs and this latest study was done with real ratties (ie the 4 legged kind!!), the benefit of COX inhibitors in the form of NSAIDs sounds like a pretty common sense, low risk, and reliable finding to aid patients' results from immunotherapy.  I am certain that my study did NOT control for NSAID use, but I imagine it is a pretty rare anti-PD1 patient who does not utilize ibuprofen to deal with arthralagias and other aches and pains the therapy produces!!  I know I certainly lived on advil and benadryl to deal with my rashes and beat up joints.  Of course, the next step will be an examination of the application in human ratties....  So, time will tell.  But, I think I'll keep taking my ibuprofen....unless Bentie makes me switch to aspirin!!!"

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.  J Clin Oncol 37, 2019 (suppl; abstr e14114)

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 BrafV600EPten-/-; 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 1cm3Results: 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

Sunday, June 30, 2019

FYI!


3 miles done. Faster than some days.  Slower than others. Just a little PSA here: running on hot pavement makes pain from neuropathies in your feet worse.  But, as Jeanne shared ~


Still...


"There is peace, even in the storm."  ~  Vincent Van Gogh

Ready for the next evolution.  (I think.) - les

Friday, June 28, 2019

I've said it before, I'll say it again - ENOUGH ALREADY! No more interferon for melanoma!!! (Or placebos - for that matter!!!)


I had to make a hard decision about utilizing interferon (or not!!) back in the dark ages of melanoma - 2010:  Oncology visit limbo.....

Since then, we have learned definitively, that interferon does NOT provide any survival benefit for melanoma patients!  There was this in 2016:   Sunbelt Melanoma Trial Final Results: No survival benefit for interferon or complete lymph node dissection in patients with a single positive SLN!

BUT, we were STILL looking at interferon as adjuvant:  ASCO 2016 - Two Adjuvant studies for Stage III/IV - with interferon vs pembro vs ipi - still recruiting 

Finally!  In  February 2017, there was this:  For Stage II/III melanoma patients: Interferon NO BETTER than observation!!!!  and in November of that year, in a discussion among Melanoma Big Dogs, this conclusion was drawn:  Review of adjuvant treatment in Stage III melanoma and "death knell" for ipi and interferon in that role!!!! 

However, Kirkwood (and others) can't seem to get the facts straight in their heads!!!  Earlier this year I wrote:  Kirkwood needs to STOP!!! NO MORE INTERFERON!!! Geeze!!!!

Now....there's this:

United States Intergroup E1609: A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon-α2b for resected high-risk melanoma.  2019 ASCO.  Rarhini, Lee, Hodi, et al.  J Clin Oncol 37, 2019.

Background: Phase III adjuvant trials reported significant benefits in relapse-free survival (RFS) for 6 FDA-approved regimens and overall survival (OS) for HDI and ipi10 versus observation or placebo. E1609 evaluated the relative safety and efficacy of ipi at 3 and 10 mg/kg compared to HDI, which was the adjuvant standard until recently. Methods: E1609 had 2 co-primary endpoints: OS and RFS; considered positive if either co-primary endpoint comparison was positive. Activated on 5/25/2011 and completed accrual 8/15/2014. A 2-step hierarchical approach evaluated ipi3 vs HDI followed by ipi10 vs HDI. Patients were stratified by AJCC7 stage (IIIB, IIIC, M1a, M1b). Based on protocol criteria, the primary evaluation was conducted using a data cutoff of 2/15/2019. Results: Final adult patient accrual was 1670; 523 randomized to ipi3, 636 to HDI and 511 to ipi10. Treatment related adverse events (AEs) Grade 3 or higher were experienced by 37% pts with ipi3, 79% with HDI and 58% with ipi10, and those of any grade leading to treatment discontinuation were 35% with ipi3, 20% HDI and 54% ipi10. AEs were mostly immune related and consistent with the known toxicity profiles of these agents. Gr5 AEs considered at least possibly related were 3 with ipi3, 2 with HDI and 8 with ipi10. First step comparison of OS and RFS of ipi3 vs. HDI utilized an ITT analysis of concurrently randomized cases (N = 1051) and showed significant OS difference in favor of ipi3. The prespecified efficacy boundary was crossed. In the 2nd step comparison of ipi10 vs. HDI (N = 989), there were trends towards improvement in OS  and RFS in favor of ipi10 that were not statistically significant. Conclusions: Adjuvant therapy with ipi3 benefits survival of resected high-risk melanoma pts; for the first time in the history of melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in the primary endpoint of OS against an active control regimen previously shown to have OS and RFS benefits, supporting early systemic adjuvant therapy for high-risk melanoma. 

Not news.  Stop with the interferon already!!!  Plus, there's this:

Multiple antigen-engineered DC vaccines with or without IFNα to promote antitumor immunity in melanoma.  Butterfield, Vujanovic, Santos, et al.  J Immunother Cancer. 2019 Apr 24.

Cancer vaccines are designed to promote systemic antitumor immunity and tumor eradication. Cancer vaccination may be more efficacious in combination with additional interventions that may build on or amplify their effects.

Based on our previous clinical and in vitro studies, we designed an antigen-engineered DC vaccine trial to promote a polyclonal CD8+ and CD4+ T cell response against three shared melanoma antigens. The 35 vaccine recipients were then randomized to receive one month of high-dose IFNα or observation.

The resulting clinical outcomes were 2 partial responses, 8 stable disease and 14 progressive disease among patients with measurable disease using RECIST 1.1, and, of 11 surgically treated patients with no evidence of disease (NED), 4 remain NED at a median follow-up of 3 years. The majority of vaccinated patients showed an increase in vaccine antigen-specific CD8+ and CD4+ T cell responses. The addition of IFNα did not appear to improve immune or clinical responses in this trial. Examination of the DC vaccine profiles showed that IL-12p70 secretion did not correlate with immune or clinical responses. In depth immune biomarker studies support the importance of circulating Treg and MDSC for development of antigen-specific T cell responses, and of circulating CD8+ and CD4+ T cell subsets in clinical responses.

DC vaccines are a safe and reliable platform for promoting antitumor immunity. This combination with one month of high dose IFNα did not improve outcomes. Immune biomarker analysis in the blood identified several predictive and prognostic biomarkers for further analysis, including MDSC.

JUST.  STOP!

And at this point....placebo?  Really????  There's this:

Ipilimumab versus placebo after complete resection of stage III melanoma: Long-term follow-up results the EORTC 18071 double-blind phase 3 randomized trial.  2019 ASCO.  Eggermont, Chiarion-Sileni, Grob, et al.  J Clin Oncol 37, 2019.

Background: Since 2015, ipilimumab (Ipi) is an approved treatment for stage III melanoma based on a significantly prolonged recurrence-free survival (RFS) (Eggermont et al, Lancet Oncology, 2015). At a median follow-up of 5.3 years, RFS and distant metastasis-free survival (DMFS), assessed by an IRC, and overall survival (OS) were prolonged in the Ipi group as compared to the placebo (Pbo) group (Eggermont et al, NEJM, 2016), despite a 53.3% (Ipi) vs 4.6% (Pbo) treatment discontinuation rate due to adverse events. Methods: In this randomized double-blind trial, eligible patients (pts) included those greater than/= to 18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) q3w for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. Here, we report the comparison between the Ipi and Pbo groups regarding the long-term efficacy outcomes using the local investigator assessments. Results: Overall, 20%/44%/36% of pts had AJCC-7 stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. Median follow-up was 6.9 yrs. The RFS, DMFS and OS benefit observed in the Ipi group was long-lasting (almost 10% difference at 7 years) and consistent across subgroups: no significant predictive factors could be detected. Conclusions: In this phase III trial, Ipi, administered at 10 mg/kg, as adjuvant therapy provided, at a 6.9 yr median follow-up, a sustained improvement in the RFS, DMFS, and OS long-term results in patients with high-risk stage III melanoma. Clinical trial information: NCT00636168

RFS

DMFS

OS

Ipi
Pbo
Ipi
Pbo
Ipi
Pbo
No. of events
273
323
247
292
173
223
5-year rate
43.9%
32.5%
49.9%
39.8%
65.2%
54.1%
7-year rate
39.2%
30.9%
44.5%
36.9%
60.0%
51.3%
Median (yrs)
2.7
1.5
5.0
2.4
NR
7.8
HR (95% CI)†
0.75 (0.63-0.88)
0.76 (0.64-0.90)
0.73 (0.60-0.89)
Log-rank p-value†
0.0004
0.0018
0.0021

Of course, Stage III melanoma peeps who were treated with ipi instead of placebo have done better!!!  DUH!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

We do not need to waste time, money and other resources on melanoma trials that utilize placebo or interferon as the comparator any longer.  While these are follow-up reports to pre-existing studies, and the data should be presented, it is unfortunate that some researchers STILL try to harken back to these variables.  NO.  MORE.  We have effective FDA approved treatments in the realm of immunotherapy, targeted therapy and intralesional therapies - across patients using them as adjuvant and to treat active disease.  Create studies that make sense.  Compare apples to apples.  No more placebo or interferon based studies!  ENOUGH!

But, through the storm....



...beauty remains, brightening the shadows, in a lighter shade of pale.  Wishing a beautiful weekend to you all.  c