Radiation for melanoma...better when combined with immunotherapy!

More and more clarifying data have researchers convinced that abscopal effects and better patient outcomes when radiation is combined with a variety therapies are very real.  Now they are working to figure out HOW it happens, so that it can happen for more people.  Here's a roundup of some of the latest research:

Here's a link to a post from an article that speaks to the benefit of combining SRS with PD1 blockade:  srs-combined-with-anti-pd1-makes-things-better! (for mice at least)

Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice.  Deng, Liang, Burnette, et al.  The Journal of Clinical Investigation, Feb. 2014. 
High dose...radiation results in direct tumor cell death...augments tumor-specific immunity, which enhances tumor control...locally and distantly.  Unfortunately, local relapses often occur [after radiation] indicating that [radiation] induced responses are inadequate to maintain antitumor immunity. Therapeutic blockade of the T cell negative regulator PD-L1 can enhance T cell effector function when PD-L1 is expressed in chronically inflamed tissues and tumors.  [These researchers] demonstrate that PD-L1 was upregulated [around the tumor] after radiation.  Concomitant with tumor regression from radiation, they noted that radiation and anti-PD-L1 worked together to reduce the local accumulation of tumor-inflitrating myeloid-derived suppressor cells (MDSCs)... {Note:  Remember, these are the bad guys that block your T cells.  In my study, the folks with high levels of MDSCs did least well, while those with the lowest levels did better.  That's why, some researchers, like Weber, are talking about depleting these cells in patients FIRST...then administering anti-PD1 or other immunotherapies!!}  So...the data acquired in this study demonstrated evidence of the interaction between radiation and T cells....and a basis for the rational design of combination therapy with immune modulators and radiotherapy.

Radiotherapy and Immunogenic Cell Death.  Golden and Apetoh.  Seminars in Radiation Oncology, Jan 2015.
In their review of radiotherapy induced immunogenic cell death....these peeps noted:  Advances in understanding the mechanisms that underlie the interplay between radiation-invoked immune responses and tumor regression are underway.  ...  The dispersion of radiotherapy-induced immune-stimulating tumor antigens released from dying tumor cells into the surround milieu is one such exploitable process that contributes to the propagation of antitumor immunity.  Downstream components of the immune system may suppress, promote or ambiguously affect antitumoral responses.

Combination of Radiotherapy and Immune Checkpoint Inhibitors.  Pilones, Vanpoiulle-Box, and Demaria.  Seminars in Radiation Oncology.  Jan 2015
...only recently [the ability of radiation to cause cell death and inflammatory reactions] has attracted the attention of immunologists seeking to induce or improve antitumor immunity.  As immune checkpoint inhibitors are becoming mainstream cancer treatments, radiation oncologists have begun to observe unexpected out-of-the-field (abscopal) responses in patients receiving radiation therapy during immunotherapy.  These unexpected responses were predicted by experimental work in preclinical tumor models and have clear biological bases.  ....evidence that radiation induces an immunogenic cell death and promotes recruitment and function of T cells within the tumor microenvironment supports the hypothesis that radiation can convert the tumor into an in situ individualized vaccine.  This property of radiation is key to its synergy with immune checkpoint inhibitors, antibodies targeting inhibitory receptors on T cells such as cytotoxic T lymphocyte antigen-4 and programmed death 1.  By removing obstacles hindering the activation and function of antitumor T cells, these agents benefit patients with pre-existing antitumor immunity but are ineffective in patients lacking these spontaneous responses.  Radiation induces antitumor T cells complementing the activity of immune checkpoint inhibitors.

Stereotactic Radiosurgery for Melanoma Brain Metastasis in Patients Receiving Ipilimumab:  Safety Profile and Efficacy of Combined Treatment.  Kiess, Wolchok, Baker, et al.  Int J Radiat Oncol Biol Phys. 2015 March. 
Ipi is a monoclonoal antibody against cytotoxic T-lymphocyte antigen-4, and has been shown to improve survival in patients with metastatic melanoma.  From 2005 - 2011, 46 patients with melanoma were given ipi and SRS for brain mets.  Radiation was a single dose.  Ipi was given at 3 or 10 mg/kg for 4 doses.  15 patients had SRS during ipi.  19 had SRS before ipi.  12 had SRs after ipi.  Patients treated with SRS during or before ipi had better overall survival and less regional recurrence.  (1 year OS = 65% vs 56% vs 40%.  1 year regional recurrence = 69% vs 64% vs 92%)  On MRI, an increase in BM diameter up to more than 150% was seen in 50% of patients treated during or before ipi, but in only 13% of patients treated after ipi.  Overall, ipi and SRS were well tolerated and concurrent delivery of ipi and SRS is associated with favorable locoregional control and possibly longer survival.  It may also cause a temporary increase in tumor size, possibly because of an enhanced immunomodulatory effect.

Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.  Victor, Rech, Maity, Rengan, et al.  Nature.  March 2015. 
Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies....Here we report major tumor regressions in a subset of patients with metastatic melanoma treated with [ipi] and radiation, and reproduced this effect in mouse models.  Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common....analysis of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T cell exhaustion.  ...Ipi (anti-CTLA4) inhibits T reg cells, thereby increasing the CD8 T cell to T reg ration.  Radiation enhances the diversity of the T cell receptor repertoire of intratumoral T cells.  Addition of PD-L1 blockade reverses T cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages ....T cell expansion.  Like the mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed.  Thus, PD-L1 on melanoma cells allows tumors to escape anti-CTLA4 based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.

From mice to ratties and back to mice again. Thanks to both, the mechanism and chain of events stimulated by radiation is becoming clear.  It certainly seems that one should get your radiation BEFORE or DURING ipi (and probably other immunotherapies as well).  While radiation kills some tumor cells directly, perhaps more importantly, it sets off an immune response caused by an influx of tumor cell antigens.  When that response is aided by either anti-PD1, anti-CTLA-4 or both, T reg suppressor cells can be blocked, CD8 fighter T cells are increased, T cell exhaustion can be reversed and the invisible shroud in which melanoma cells like to hide, evaporates.  Despite the incredulity that must be swallowed to acknowledge that a somewhat mystical, minute, but deadly cellular war is being waged within my own body.....it sounds good to me!!! - c

Nivo (Opdivo) with radiation = better for melanoma patients with brain mets

Combining nivolumab (Opdivo) with radiation therapy may provide better disease control and prolong overall survival in patients with melanoma whose disease has metastasized to the brain, compared with standard current treatment....according to new report from onclive.....

http://www.onclive.com/web-exclusives/combining-nivolumab-with-radiation-shows-promise-in-melanoma-patients-with-brain-mets 

Combining nivolumab (Opdivo) with radiation therapy may provide better disease control and prolong overall survival (OS) in patients with melanoma whose disease has metastasized to the brain, compared with standard current treatment, according to a recent retrospective analysis.

Researchers of Moffitt Cancer Center analyzed data from 26 patients with 73 brain metastases from two separate prospective clinical trials at the center. Radiation was administered prior to, during, and after nivolumab in 33 lesions (45%), 5 lesions (7%), and 35 lesions (48%), respectively.

According to study results, Kaplan-Meier estimates for local brain metastases control following radiation were 91% after 6 months and 85% after 12 months. Median OS from the date of stereotactic radiation and nivolumab initiation was 11.8 and 12.0 months, respectively, in patients receiving nivolumab for unresected disease. Median OS was not reached in patients treated in the resected setting.

“This is the first study to assess outcomes of nivolumab and stereotactic radiation for the management of brain metastases,” lead study author Kamran A. Ahmed, MD, a resident in the Department of Radiation Oncology at Moffitt, said in an interview with OncLive. “We found that overall survival and local control in this patient cohort was improved over historical controls, suggesting nivolumab and radiation may have a synergistic effect in the management of melanoma brain metastases.”

These findings are important, as there is a great need for improvement in the management of patients with melanoma brain metastases, said Ahmed. Historically, patients with melanoma brain metastases survive 4 to 5 months, on average.

“About half of advanced melanoma patients will develop brain metastases,” said Ahmed. “Improving outcomes in these metastatic melanoma patients who have the worst prognosis is very important.”

In the study, all brain metastases were treated with stereotactic radiosurgery (SRS) in a single session except for 12, who were treated with fractionated stereotactic radiation therapy, 9 of whom were in the postoperative setting.

One patient experienced grade 2 headaches following SRS with symptomatic relief with steroid treatment. No other treatment-related neurologic toxicities or scalp reactions were reported.

Eight (11%) local brain metastases failures with a >20% increase in volume were noted in the study. Of these lesions, hemorrhage was noted in 4 and edema was noted in 7.

“We found nivolumab combined with either radiation treatment before, during, or after was very well tolerated,” said Ahmed. “There were no neurotoxicity or cutaneous side effects, which we would not expect with radiation treatment alone. We know the 2 agents can be combined safely based on this study.”

The current standard of care for melanoma brain metastasis is focal radiation treatment for patients with limited disease, and whole brain radiation for patients with advanced disease. As nivolumab and other immunotherapies become more commonly used in melanoma, it is important to understand how they will work in conjunction with radiation, says Ahmed.

Treating brain metastases requires a multidisciplinary approach, especially in melanoma. Cutaneous oncologists, radiation oncologists, and neurosurgeons, he adds, need to work together to determine optimal treatment plans.

“Multiple systemic agents have proven to have a survival benefit in advanced melanoma, and it is important to see how these therapies interact with radiation treatment as well as surgery,” said Ahmed. “What we’ve seen here at Moffitt is that immunotherapy and radiation treatment can be safely combined, with improved local and distant brain control as well as overall survival in patients with brain metastases.”

Following this retrospective analysis, there are plans to evaluate nivolumab and radiation therapy in the prospective setting to better understand the potential synergistic effects between the two.

“A lot of work needs to be done to see how we can improve outcomes in the management of melanoma brain metastases, but what we’ve learned here is a good start,” said Ahmed.

Nivolumab is currently FDA approved to treat non–small cell lung cancer, renal cell carcinoma, and melanoma.

Wonder if this rattie was included in this retrospective.  I had a brain met treated with one session of SRS in April 2010 and started Nivo at Moffitt in December of 2010....with one additional ????? lesion in my brain per the MRI on entry...(Here is the story of that conundrum:  Melanoma Neverland)...that was no longer seen on MRI's after three months of treatment.  As happy as I am that that was the case and that whoever these ratties may be, are are leading the way with the info produced here....isn't it strange that the ratties are NEVER told?????!!!! - c

CONCURRENT radiation and immunotherapy for brain mets is BEST!!!! (yes, AGAIN!!!)

"I know, I know!!!!"   I keep ranting about this.  And I will continue until it seeps into the pores of all melanoma (as well as NSCLC and renal cell carcinoma) patients and docs!!! Here are just a few zillions rants, posts, and data:  Yes, you SHOULD COMBINE radiation and immunotherapy!!!!
Now, there's this ~

Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma. Chen, Douglass, Kleinberg, et al.  Int J Radiat Oncol Biol Phys. 2018 Mar 15. 

To characterize the effect of concurrent stereotactic radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint inhibitors on patient outcomes and safety in patients with brain metastases (BMs).

We retrospectively identified metastatic non-small cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We included SRS-SRT patients who were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune checkpoint inhibitors on active or unreported clinical trials were excluded, and concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2 weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events, and new BMs.

A total of 260 patients were treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of greater than/= to 3 new BMs after SRS-SRT. Median OS for patients treated with SRS-SRT, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone and compared with nonconcurrent SRS-SRT and ICI on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI or after ICI.  Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.

Here folks looked at patients suffering from brain mets due to NSCLC, melanoma, and renal cell carcinoma.  Between 2010 and 2016, these peeps were treated with SRS-SRT and given either ipi, nivo or pembro.  CONCURRENT immunotherapy was defined as the meds having been given within 2 weeks of the radiation.  There were three groups:  1) those treated with radiation alone, 2) those treated with radiation and NON-concurrent immunotherapy, 3) and those treated with radiation and CONCURRENT immunotherapy.  260 patients were given radiation to 623 brain mets.  181 had radiation alone.  70 patients got radiation and immunotherapy with 35% of those attaining radiation concurrent with immunotherapy.  Overall survival for radiation alone = 12.9 months.  OS for radiation and NON-concurrent immunotherapy = 14.5 months.  OS for radiation with CONCURRENT immunotherapy = 24.7 months.  This was true no matter if the radiation was given before or after the immunotherapy....AND....wait for it....CONCURRENT administration of immunotherapy and radiation did NOT cause increased immune side effects NOR an increased rate of neurologic problems!!!!!!!!!!!!!!!!!!!  However, CONCURRENT immunotherapy and radiation DID decrease development of additional brain mets later!!!!

Come on folks!!!  This matters.  This is important.  This changes SAVES lives!!!  Do NOT settle for less.  If you have brain mets, demand CONCURRENT immunotherapy and SRS!!!!  There is more than enough proof.  It makes a positive difference!!! - c

Review of abscopal responses after radiotherapy in melanoma patients

A systematic review of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab.  Chandra, Wilhite, Balboni, et al.  Oncoimmunology.  May 2015.

"Case reports and preclinical data suggest radiotherapy and immunotherapy may synergize to generate 'abscopal' responses outside the radiation field.  This phenomenon remains relatively unexplored.... We evaluated 47 consecutive metastatic melanoma patients treated with ipi and 65 courses of radiation.  Responses of index lesions outside the radiation field were compared before and after radiotherapy...  Median survival was 28 months, with an estimated 20% of 5 year survival.  Index lesions shrank in 7 instances prior to radiation therapy (11%), compared with 16 instances after radiation therapy (25%); in 11 of the later instances (69%), the index lesion had been increasing in size prior to radiotherapy.  In 68% of cases, radiotherapy was associated with an improved rate of index lesion response....  Our...review...suggests that a subset of patients may have more favorable out-of-field responses following treatment with radiation. Interestingly, we found that multiple fraction radiation regimens were associated with a more favorable response.  These results are encouraging regarding potential synergies between radiation and immunotherapy, but suggest that attention and even prospective testing of radiation parameters critical to producing abscopal effects...would be of value."

Cool!  Now keep in mind that this is talking about 'abscopal' responses....not just a general enhancement of effectiveness when immunotherapy is combined with radiation....as this post was referring to:  Why immunotherapy is better with radiotherapy....

Here's an early post about abscopal responses:  Abscopal effects of radiotherapy

An older post about ipi, radiation, increased effect and abscopal responses:  ipi and radiation: a good combo for melanoma

Finally, there have also been abscopal responses noted with intralesional therapy...which do not involve radiation:  asco 2015: intralesional therapy for melanoma

Obviously, there is much more to learn about the mechanisms that come into play when immunotherapy and radiation are  combined...both for generally increased benefit and abscopal responses in particular.  At least folks are now paying attention and trying to figure it out rather than arguing about whether it is real. Hang in there, ratties.  You have taught us all amazing things!   - c

Melanoma brain mets respond best when radiation and immunotherapy are given TOGETHER!!! What about melanoma brain mets when treated with BRAFi and radiation????

I know, I know!!!  I've said this a million times.  Radiation administered ~ CONCOMITANTLY, CURRENTLY, AT THE SAME TIME, IN COMBINATION WITH ~ immunotherapy ~ provides much better outcomes for folks with melanoma brain mets.  Here's my last report with a link to a zillion others:  March 2018 - CONCURRENT radiation and immunotherapy for brain mets is BEST!!!! (yes, AGAIN!!!)

Now, there's this ~

Impact of simultaneous radiotherapy in melanoma patients treated with pembrolizumab in the French early access program. Saiag, Mortier, Dutriaux, et al. ASCO Meeting, 2018.

Information on the use of radiotherapy in anti-PD-1 monoclonal antibody-treated melanoma pts is limited although some data support a synergistic effect.  We investigated the influence of simultaneous radiotherapy in a multicenter ambispective cohort of advanced melanoma patients initiating pembrolizumab between May 2014-Sept 2015. Palliative or curative intent of radiotherapy was recorded.   

663 pts (151 pts with brain metastases) were included in 40 French centers, with 125 pts (19%) receiving simultaneous radiotherapy (43 pts with greater than/= to1 brain metastasis, 82 without). No significant difference in baseline LDH level, ECOG performance status, N of metastatic sites, previous treatment lines or post-progression therapies was observed between pts who did or did not receive radiation. As compared to pts without brain metastases, radiotherapy was performed in brain metastases pts closer to initiation of pembrolizumab (median 1.1 m vs 3.7 m) and more frequently with a curative intent (72% vs 37%). Globally, OS was longer in radiated vs non-radiated pts (median 18.9 m vs 12.5). This benefit was mainly driven by the pts with brain metastases (OS: median 26.0 m vs 6.0 m) (PFS: 6.4 m vs 2.5 m). No significant difference was seen for OS in radiated pts without brain metastasis, who were mainly radiated later and for palliative reasons and had shorter PFS (2.8 vs 3.4 m).  Simultaneous radiotherapy may enhance efficacy of anti-PD1 therapy, particularly when initiated early and in brain metastases pts. 

Here, from an initial 663 melanoma patients, 125 patients were given pembro with simultaneous radiation.  43 of these had brain mets while 83 did not. Overall survival was better in radiated patients (18.9 months vs 12.5 months) though this benefit was driven mostly by the brain met folks who demonstrated an OS of (26 months vs 3.7 months).  However, "No significant difference was seen for OS in radiated pts without brain metastasis, who were mainly radiated later and for palliative reasons and had shorter PFS (2.8 vs 3.4 m)."  So the conclusion was: "Simultaneous radiotherapy may enhance efficacy of anti-PD1 therapy, particularly when initiated early and in brain metastases pts." 

Okay, #1, this told us what we already knew:  Immunotherapy works best for folks with brain mets when given WITH radiation therapy!!!   But, it seems possible (at least to me) that that same rule may apply to folks with melanoma elsewhere.  Because...though in this study the folks with radiation given to sites that were NOT brain mets did not see any particular benefit of the pembro/radiation combo...the authors acknowledge that those patients were "radiated later and for palliative reasons".  I'm just wondering if it is possible that had THOSE patients been given radiation WITH their pembro - would they have done better, too????

And just when we think we have that all figured out....there's this ~

BRAF V600 Mutation and BRAF Kinase Inhibitors in Conjunction With Stereotactic Radiosurgery for Intracranial Melanoma Metastases: A Multicenter Retrospective Study.   Mastorakos, Xu, Yu, et al.  Neurosurgery. 2018 May 29.

The BRAF mutation has been identified as a potent target for the treatment of metastatic melanoma and BRAF inhibitors (BRAFi) have demonstrated promising results against melanoma brain metastases (BM).  In this multicenter retrospective cohort study, 198 patients with known BRAF mutation status and treated with stereotactic radiosurgery (SRS) between 2011 and 2015 were identified. 

The median survival after the diagnosis of BM in patients with BRAF mutation who received BRAFi was increased compared to survival in patients with wild-type BRAF (BRAF wt).  BRAF mutated Patients who received BRAFi following SRS had improved survival compared to patients who received it before or concurrently. PD-1 inhibitors improved survival, with more pronounced effect in patients not carrying the BRAF mutation. Among the patients who were treated with BRAFi, 10.4% developed intracerebral hematoma (ICH), in comparison to 3% of patients who were not treated with BRAFi.

In the setting of widespread use of BRAFi, the presence of a BRAF mutation is an independent predictor of better prognosis in patients with melanoma BM that underwent SRS. The effect of BRAFi is optimal when treatment is initiated at least 1 wk following SRS. BRAFi may increase the frequency of asymptomatic ICH.

So, here, folks with BRAF positive melanoma did better when treated with BRAF inhibitors than did those who were wild type.  (Is that really news?)  BRAF positive folks also did better when they were given BRAFi AFTER radiation to their brain mets, rather than those who were given BRAFi before or  concurrently.  Administration of BRAFi one week after radiation was best.  However, folks given BRAFi did have an increased chance of developing some bleeding in the brain.

Clear as mud??  Not really, huh?  Well, that's melanoma for you.  Not sure the BRAFi/radiation report is an absolute yet.  So at this point, zap your brain mets, start BRAFi the following week, and make sure your doc observes you closely for ICH.  But, we certainly have more than enough info on immunnotherapy and radiation in melanoma brain mets to know for sure:  Get yo SH!# TOGETHER!!!  Hey, I like that little pneumonic!!!  Meaning, get your immunotherapy WITH your radiation treatment!!!

Hang tough ratties!!!  Cause melanoma don't play and the whole thing is just cray cray!!! - c

Anti-PD-1 and radiation...good combo for brain mets.....AGAIN!!!!! Again.....

Y'all know I've been yelling about the improved outcomes patients can attain for brain mets when targeted radiation (SRS or Gamma knife) is paired WITH immunotherapy:  Here's just a few of my rants and LOTS of data:  Radiation and Immunotherapy...better together!

Now there's this:

Radiation and PD-1 inhibition: Favorable outcomes after brain-directed radiation. Pike, Bang, Ott, et al. Radiother Oncol. 2017 Jun 26.

Patients with metastatic melanoma, renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC) are increasingly treated with immune checkpoint blockade targeting the programed death (PD)-1 receptor, often with palliative radiation therapy. Outcome data are limited in this population. We retrospectively reviewed consecutive patients with metastatic NSCLC, melanoma, and RCC who received radiation and anti-PD-1 therapy at four centers.

We identified 137 patients who received radiation and PD-1 inhibition. Median survival from first PD-1 therapy was 192, 394, and 121  days for NSCLC, melanoma, and RCC patients. Among 59 patients who received radiation following the start of PD-1 blockade, 25 continued to receive PD-1 inhibition for a median of 179days and survived for a median of 238 additional days. Median survival following first course of radiation for brain metastases was 634 days. Melanoma patients received brain directed radiation relatively less frequently following the start of PD-1 inhibitor treatment.

Incorporation of palliative radiation does not preclude favorable outcomes in patients treated with PD-1 inhibitors; patients irradiated after the start of PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of note, patients irradiated for brain metastases demonstrate favorable outcomes compared with historical controls.

It is still not easy nor perfect....but it's something!!! - c

Immunotherapy with SRS does NOT increase risk of radiation necrosis in melanoma brain mets!!!

We already know that folks who get immunotherapy WITH (or as soon as possible relative to) SRS [stereotactic radiation] therapy for brain mets do best.  Here's a post with multiple links that covers that and then some: Anti-PD-1 works best with SRS for brain mets in melanoma, Don't wait to add anti-PD-1 to SRS for brain mets, etc, etc!!!!!

Yet, patients are STILL being advised BY THEIR ONCOLOGISTS, "Oh, my goodness, no!!  We can't do both immunotherapy and SRS to brain mets at the same time.!  It would be too toxic.  It would increase the risk of radiation necrosis!"

Now, radiation necrosis is a real problem.  It is a complication that arises for far too many.  However, combining radiation with immunotherapy does NOT increase the risk!  Check out this review of 137 patients and their 1,094 brain lesions:

Radiation necrosis with stereotactic radiosurgery combined with CTLA-4 blockade and PD-1 inhibition for treatment of intracranial disease in metastatic melanoma. Fang, Jiang, Allen, et al.  J Neurooncol. 2017 May 12.  

Immune checkpoint inhibitors have demonstrated remarkable benefits in cancer patients. However, concern regarding toxicity in the setting of stereotactic radiosurgery (SRS) is often raised. In this study, we characterize radiation necrosis (RN) following immunotherapy and SRS. Melanoma patients treated with SRS and anti-CTLA-4 and/or anti-PD-1 at our institution from January 2006 to December 2015 were retrospectively reviewed. Overall survival (OS) and time to RN were assessed using Kaplan-Meier analysis. Logistic regression and Cox proportional hazards analyses were performed to identify predictors of radiation necrosis-free survival (RNFS) and RN risk. One-hundred thirty-seven patients with 1094 treated lesions over 296 SRS sessions were analyzed. Median follow-up was 9.8 months from SRS. Rate of RN was 27% of patients with median time to RN of 6 months. Median OS from SRS treatment was 16.9 months. RNFS at 6 months, 1 and 2 years was 92.7, 83.0, and 81.2%. Treatment with chemotherapy within 6 months of SRS was associated with worse RNFS at 1 year. On multivariate analysis, chemotherapy within 6 months and increased number of lesions treated were predictive of increased RN risk, whereas immunotherapy type and targeted therapy were not predictive. Median target volume of lesions that developed RN was greater than that of lesions that did not. Concurrent treatment with chemotherapy, larger size and number of lesions treated were predictive of RN. Immunotherapy type and timing proximity to SRS were not associated with RN risk.

So, this review of real ratties demonstrates that having chemo (OMG????!!!!), larger sized brain lesions, and a greater number of lesions treated DOES increase the risk of radiation necrosis - giving immunotherapy (ipi or anti-PD-1) and timing proximity to SRS treatment does NOT!!!!!

Could we get some nit-wit oncologists/radiation oncologist to read their own professional journals....or this blog?  Well, if you get told something similar to the little talk outlined above....PRINT and DELIVER this report to them! Hang tough, dear ratties! - c

Primer for Current Melanoma Treatments - New and Improved Version 2022!!!!

Originally posted in 2017, sadly, this primer has needed little in the way of updates since.  Still, there have been a few FDA approvals, meds I didn't include in the first rendition, and some news in the research so it is getting a reboot. Initially created to save re-writes for those in need, I still answer melanoma questions on boards or via email at least every other week, but want to emphasize that this is not an all inclusive listing.  Rather, this is a basic guide to use in starting your research or discussions with your provider regarding melanoma care.  As recently, as 2010, NONE of the current, most effective treatments for melanoma were FDA approved.  Since then, doctors have become more knowledgeable about consistently offering and better skilled in managing these treatments.  Still, it is essential that you be seen by an oncologist who specializes in, or at the very least, has treated many patients with melanoma.  Sometimes a picture is worth a thousand words ~ 

Here we go:

SURGERY

Surgery remains a good choice for many melanoma patients.  Clearly this is the case for a new cutaneous lesion.  Surgery results in an immediate decrease in your tumor burden - almost always a good thing.  However, with data showing good results in NEO-adjuvant treatment, the possibility of using intralesional therapy, or if you are looking for a clinical trial, there are times when measurable disease is needed, so a discussion of these things before surgery is important.  However, for patients with advanced disease decreasing tumor burden through surgery remains an important option for increased survival.  This 2019 report addresses some of the conundrum:  Cut it out!!! Prolonged overall survival following metastasectomy in Stage IV melanoma 

RADIATION

Radiation, when combined with immunotherapy or targeted therapy, can be a very good treatment option for melanoma.  Together, radiation and systemic therapy can illicit responses that are greater than either treatment used as a single agent.  However, targeted radiation (SRS - stereotactic radiation or Gamma Knife) is the most effective whether you are talking about brain tumors or lesions in the body.  We have learned that whole brain radiation (WBR) is not the most effective way to treat melanoma and can lead to debilitation.  While there are those who must avail themselves of this treatment due to extreme circumstances, it should not be the first recommendation right out of the box for those with brain tumors.  Even multiple brain mets can be treated simultaneously with SRS.   Here are zillions of reports regarding the effectiveness of using radiation WITH immunotherapy: Radiation WITH immunotherapy  Here is a report from 2019 regarding the use of radiation prior to targeted therapy:  Better melanoma results with radiation BEFORE BRAFi (at least in this report)

IMMUNOTHERAPY

These are treatments that push our immune systems into action.  Side effects (as you might imagine) are usually related to an 'over activation' of the immune system.  Common side effects include - fatigue, rashes, joint pain.  More complicated side effects are inflammation of the lungs (pneumonitis) and colon (colitis) with difficulty breathing and wheeze or diarrhea and abdominal discomfort, respectively.  Patients can experience problems with thyroid function and other glands of the endocrine system.  Responses take time.  Experts are known to advise other docs to be 'patient with the patient!'  Immunotherapy works best with the lowest tumor burden.

Old school immunotherapy

Interferon

Discovered in 1957, interferons are a type of signaling proteins released by cells in response to viruses, bacteria, parasites, and tumors that help rally the immune response of the body against these invaders. In the early 1980's researchers and pharma were finally able to produce interferon for use as a medical therapy. There are many forms, used in treating various conditions (some more effectively than others) from multiple sclerosis to leukemia to melanoma. Often given as subcutaneous injections (though there are eye drops and inhalation forms), interferon causes significant side effects with fatigue, flu-like symptoms, hair loss, pain, depression and increased risk of infection due to neutropenia (decreased white cells) being common. Unfortunately, we have learned that in melanoma, interferon has a clinically insignificant effect on progression free survival as well as overall survival.

IL-2 (Interleukin 2) also known as aldesleukin, proleukin, and/or sylatron

Similarly, IL-2 is a signaling molecule that directs the actions of white blood cells in getting rid of invaders. Isolated in 1979, by the early 80's pharma (Ceta, Amgen, Roche) were in a mad dash to get a drug to market. It was FDA approved in 1992. It has been used in the treatment of HIV, renal cell carcinoma, and melanoma. Though it can be injected subcutaneously on an outpatient basis, in melanoma it is most often given in an IV infusion, with side effects (extreme swelling, rash/peeling skin, hallucinations, among other horrors) such that patients must be in the hospital, in an intensive care setting, for infusions that are given every 8 hours for up to 15 doses or as the patient can tolerate. It is also used in a low dose regimen with old school TIL therapy as a way to jump start the immune system after chemo has been given to eradicate existing regulatory T cells and new T cells grown from the patient's tumor have been infused.  See this 2021 report:  TIL - A report out of ASCO 2021 and incredible words from one of Melanoma's Most Fearless and Inspiring Leaders  It is also being studied as an intralesional (see below). Ultimately, we now know that the use of high dose IL-2 in melanoma can produce a complete response in about 5-6% of the patients, with some of those responses being durable (lasting).  

Current Immunotherapy (also referred to as Check Point Inhibitors)

Ipilimumab (Brand name = Yervoy, slang = 'ipi') – anti-CTLA-4 monoclonal anti-body

Ipilimumab is a monoclonal anti-body that is used to restart the immune system by targeting CTLA-4, a protein receptor that actually turns the immune response OFF!!! The concept of using anti-CTLA-4 antibodies to treat cancer was developed by Dr. James Allison, for which he was awarded a Nobel Prize in 2014.  It was approved for melanoma (Stage IV or unresectable Stage III) in 2011. It was approved as an adjuvant treatment for melanoma in 2015. However, we have since learned that melanoma patients with advanced disease respond much better to the ipi/nivo combo rather than ipi as a single agent and folks in need of adjuvant therapy do much better with one of the anti-PD-1 products.  Ipi as a single agent was administered via an IV infusion every 3 weeks, for a total of 4 doses, at 3mg/kg for Stage IV patients and 10mg/kg for adjuvant therapy. Some adjuvant treatment plans continued ipi at that same dosage but every 12 weeks for up to 3 years. Melanoma patients given ipi can attain a response rate of about 15%. Responses can be durable.   Patients experience more side effects with ipi than they do with anti-PD-1 products and ipi is the bad boy of side effects in the ipi/nivo combo.  Ipi at 10mg/kg produces more side effects than ipi at 3mg/kg.  The ipi/nivolumab combo was FDA approved in (2015).  In that treatment, patients are given an infusion of ipi at 3 mg/kg after nivo at 1mg/kg is given on the same day, every 3 weeks, for 4 doses, followed by one year of nivo as a single agent. 

Anti-PD-1 (Brand names = Opdivo and Keytruda, Nivolumab and Pembrolizumab respectively.)

      

Background:  PD-1, also called programmed cell death protein 1, is a membrane protein and a T cell regulator, first discovered to be an immune checkpoint in 2000.  PD-1 is expressed on the surface of activated T cells, B cells and macrophages (white cells that can be involved in tissue repair or digestion of debris or pathogens). Compared to CTLA-4, PD-1 is keyed to specific tissues with the PD-L1 ligand, while CTLA-4 is less specific.

PD-L-1 is a ligand present on the surface of melanoma tumors (as well as some others) that can bind to infiltrating t-cells and turn them off!!

  

ANTI-PD-1 (the drugs) are monoclonal antibodies that block the switch on T cells so that PD-L1, on the surface of melanoma tumor cells, does NOT bind with them and turn them off....thereby allowing these cells to carry on and destroy melanoma tumors.

Sometimes pictures tell the story better:

    Nivolumab: (Brand name = Opdivo, slang = 'nivo') - anti-PD-1 monoclonal antibody

I wrote a little story about the development of nivo here, but basically, in 2014 Nivo was approved for the use in advanced melanoma patients only AFTER they had failed ipi and, if BRAF positive, BRAF inhibitors as well.  In November 2015 it was approved as a first line drug for unresectable or advanced melanoma BUT you had to be BRAF positive.  (A cosmically ridiculous judgement since we already had studies proving that BRAF status made little to no difference in response!!)  Finally, in 2016, based on the results of the  Checkpoint-067 study, nivo was approved for use alone or in combination with ipi, in advanced melanoma patients, no matter BRAF status.  And in 2017, it gained approval as an adjuvant treatment option.  This was seriously good news!!!  It meant even if you are Stage IV with all tumors removed (or zapped) - you can still take nivo.  Or, if you are Stage III with melanoma that went to your lymph nodes - you can take nivo!   Since then, nivo has also been approved for use in NSC lung cancer, urothelial and renal cell cancers, gastric and esophageal cancers, hepatocellular carcinoma as well as head and neck cancers.

      Pembrolizumab: (Brand name = Keytruda, slang = 'pembro') - anti-PD-1 monoclonal antibody

Pembro was similarly approved for advanced melanoma in 2014.  Since then it has been approved in various algorithms for NSCLC, head and neck squamous cell cancers, Hodgkins lymphoma, and endometrial cancers.  In 2019, it was approved for adjuvant treatment of Stage III melanoma and for Stage II adjuvant melanoma in December of 2021.

Response rate and side effects for advanced melanoma patients:

Both anti-PD-1 drugs as single agents effect about a 40% response rate in melanoma. They can work in the brain and the body.  Median time to response is about 3 months.  But, there are outliers, with documented responses, that do not occur until 6 - 9 months.  Here's a cool graph...

Here's a post with more info: Time to Response...Ipi vs Nivo and ipi 

Responses to immunotherapy have proven to be durable!!!   This post includes neat charts regarding response and durability to Pembro: Dr. Daud review from ASCO 2016   There is this from 2020:  Response after discontinuation of anti-PD-1 in melanoma patients whether due to disease progression, side effects or choice  And this from 2021:  ASCO 2021 - Outcomes of treatments on advanced disease - Reasons for HOPE!!!!!

Side effects are similar for both drugs and are those typical for immunotherapy, but less severe than those encountered with ipi.  As expected, the ipi/nivo combo has greater side effects than when nivo or pembro are used alone.  On the topic of side effects...they SHOULD be treated!!!  As quickly as possible.  At times, a break from medication and immunosuppressive drugs are required.  While oncologists not familiar with immunotherapy may fear decreased therapeutic response if steroids are used...the preponderance of the data indicates that THIS IS NOT THE CASE!!!!  Clearly, one should not take immunosuppresive drugs unless absolutely needed.  Many patients require varying doses of steroids in order to tolerate necessary, life saving melanoma treatments  and go on to do well!  Further, folks with pre-existing autoimmune disease can be managed on immunotherapy and gain a response as well.  Here are a zillion reports on all of that jazz:  What to do about immunotherapy if you need steroids or have a pre-existing autoimmune disease?

Dosing:

When Pembro is used as a single agent = is dosed at 2mg/kg with max of 200 mg IV every 3 weeks - for one year as adjuvant, end point undefined for advanced melanoma patient.  Nivo as single agent = is dosed at 240 mg IV every two weeks or 480mg IV every 4 weeks - for one year as adjuvant, endpoints vary for advanced melanoma patients. When ipi is combined with nivo, response rates in melanoma rise to 50+%, though side effects increase as well - mostly due to ipi.  For the combo, dosage is:  nivo at 1 mg/kg followed by ipi at 3 mg/kg on the same day, every 3 weeks for 4 doses, then nivo alone at 240 mg q 2 wks or 480 mg q 4 wks. endpoint varies. Many patients cannot tolerate all 4 doses of the ipi/nivo combo due to side effects.  However, outcomes can be good even if you have to stop early. Here's a report from ASCO 2016:  ASCO 2016 - Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!  Further, the ASCO 2021 data (link above) notes "Clinical benefit response (CBR) after 1 or 2 doses of I/N may be predictive of long-term survival in advanced stage melanoma. Patients who have CBR after 1 or 2 doses of I/N may achieve a similar survival benefit with fewer doses of I/N."  Finally, most folks who cannot tolerate the combo can go on to tolerate nivo alone, once their side effects are brought under control with a medication break and/or steroids.  

   Anti-PD-1 (Opdivo) plus Anti-LAG-3 (Relatlimab):

In March of 2022, Relatlimab (an anti-LAG-3 drug) was approved in combination with Nivolumab for advanced melanoma patients in the form of a new drug combo - Opdualag.  Here is a report that covers lots of pertinent data- FDA approves Relatlimab plus Nivolumab (Opdivo) for advanced melanoma patients - the down and dirty on Opdualag!!!!

TARGETED THERAPY

At this point in melanoma, the only approved targeted therapy is for patients whose tumor is positive for the BRAF V600 mutation.  About 50% of melanomas are.  However, researchers are looking at drugs that could target other points in the molecular pathway of melanoma.  This diagram shows what I mean by "pathway"...

A Melanoma Molecular Disease Model (See the link below for credit and more info)

Here's just one example from March of this year:  What tangled 'paths' we weave: Nilotinib for KIT mutated melanoma and Buparlisib for the PI3K pathway in melanoma brain mets

But....for current purposes....I am focusing on the BRAF mutation.  Here's a post I made a bit ago that really breaks down what BRAF is, what it means in melanoma, and how the drugs work:  BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!

Usually when we combine drugs, we end up with increased side effects. However, in the case of BRAF targeted therapy we now know that BRAF inhibitors should ALWAYS be given with a MEK inhibitor.  Strangely enough, when the combo is given, patients experience better response rates, DECREASED side effects, and DECREASED rates of tumor work-around.  The only exception is when MEK inhibitors are used as a single agent in specially mutated patients.

DRUGS, administration, and side effects:

BRAF inhibitor (BRAFi) drugs include:  Vemurafenib (Zelboraf), Dabrafenib (Tafinlar), Sorafenib (Nexavar), and Encorafenib (Braftovi)
MEK inhibitors (MEKi) include:  Trametinib (Mekinist), Cobimetinib (Cotellic) and Binimetinib (Mektovi)

These drugs are administered orally.  So that's super cool.  Dosing depends on the particular drug.
Side effects include joint pain, rashes, extreme sun sensitivity, development of benign skin cancers, fevers and sometimes liver toxicity.

EFFECTIVENESS and tumor work-around:

For patients who are BRAF positive, BRAF inhibitors combined with a MEK inhibitor have impressive response rates, clearing tumors rapidly, and often completely, in about 70-80% of patients and are effective in the brain and body. However, those responses are not very durable, with most tumors learning to work around the inhibition in about 7-9 months. BUT!!!!  By using an "alternate dosing schedule" (one that is varied, rather than absolute with an 'every so many hours daily' dosing pattern), combining BRAFi with MEKi, as well as the development of the newer drugs that time can be stretched out a bit.  Furthermore, despite the statistics, there are some melanoma peeps whose melanoma has been successfully managed for years on BRAF/MEK combo's!!  Finally, some melanoma specialists use BRAF/MEK combo's in BRAF positive patients, to rapidly decrease the tumor burden, then switch the patient to slower acting, but more durable immunotherapy.  Picking which targeted therapy to use can be difficult.  Here are two posts that attempt to pull response rates and PFS out of the data ~

From 2018:   Well, okie dokie!!! BRAFTOVI/MEKTOVI (Seriously guys??? That's the name???!!!) Encorafenib with Binimetinib approved for melanoma.

From 2019:  BRAF/MEK combo's for melanoma analyzed ~

IMMUNOTHERAPY COMBINED WITH TARGETED THERAPY -

In 2020, the PD-L1 blocking antibody Atezolizumab (Tecentriq) combined with Cobimetinib (Cotellic) and Vemurafinib (Zelboraf) was FDA approved.  Here is a report from 2019 that links to other reports on combining targeted and immunotherapies and includes data from the early atezo/BRAFi/MEKi trials - Treating melanoma by COMBINING targeted therapy AND immunotherapy!

INTRALSIONAL (also referred to as 'intratumoral') THERAPY

Intralesional drugs include (but are not limited to):

T-VEC - also called OncoVEX, Imlygic, or Talimogene Laherparepvec - uses the herpes virus with GM-CSF and is the only intralesional currently FDA approved (2015)  However, the following (and others) have been used in clinical trials:
CAVATAK - derived from the Coxsackievirus
T-VEC - also called OncoVEX, Imlygic,  or Talimogene Laherparepvec - uses the herpes virus with GM-CSF
PV-10 - derived from Rose Bengal
HF10 - also derived from HSV
SD101 - a TLR9 agonist
IL-2 - see note above, is also being used

These drugs are injected directly into a relatively superficial melanoma tumor.  They have been found to be effective in not only eradicating the tumor into which they have been injected, but 'by-stander' lesions as well. Researchers feel that they have the most promise when they are combined with a systemic treatment like immunotherapy.  I summarized response rates, side effects, and pretty much everything else current about these drugs in these posts which include many links within them: 

From 2021 - Intralesionals for melanoma - some new reports

Out of ASCO that year - Intratumoral or Intralesional therapy for melanoma - again. Yep, AGAIN!!! ASCO 2021, here we go!

                                     -------------------------------------------
I hope this primer will continue to be a helpful jumping off point for those in need.  What has served me best in attaining effective treatment for my melanoma has been seeking out a melanoma specialist (or at least an oncologist who cares for many melanoma patients) and never being afraid to ask questions. Asking this question of my doctor may have been the most beneficial:  "What treatment would you recommend if it were YOU or your brother, sister, wife, father, mother.... in need?"

I wish you all my very best. Hang in there.  And as ever, with enduring thanks to the ratties! - love, c

P.S. If all the acronyms are driving you crazy, here's a post that defines at least some of them:  Melanoma abbreviations ~ and random thoughts on posting melanoma crap-ola....
P.S.S.  A sense of humor really does help!!  AND FINALLY - while not all inclusive, this post from 2019 includes a list of world class melanoma specialists:   Internationally renowned melanoma specialists:  - c

Radiation of lymph node basin - not so helpful if that is all that is done

While we have learned that radiation COMBINED with systemic therapy helps melanoma patients in both PFS and OS.  Radiation alone?  Not so much...at least when used on the affected lymph node basin as an adjuvant treatment.  Here's the latest:

The influence of postoperative lymph node radiation therapy on overall survival of patients with stage III melanoma, a National Cancer Database analysis.  Danish, Patel, Switchenko, et al.  Melanoma Res. 2016 Aug 29.

Recently, TROG 02.01 results showed that in stage III melanoma patients with nodal metastasis, adjuvant radiation to lymph node basin after nodal dissection improves lymph node field relapse without an overall survival (OS) benefit. However, this trial was neither designed nor powered to detect an OS difference. In the present study, we analyzed patients in the National Cancer Database (NCDB) with stage III melanoma with pathologically involved nodes and compared survival outcomes of adjuvant radiation and no-radiation cohorts. Inclusion criteria were as follows: age at least 18 years; diagnosed 2003-2011; surgery to regional lymph nodes; pathologically involved lymph nodes; and American Joint Committee on Cancer stage (IIIA-C). We used propensity score matching analysis to compare the OS of patients with similar baseline demographic, clinical, and pathologic characteristics who received adjuvant radiation and no adjuvant radiation. Overall, 912 patients were analyzed with an average age at diagnosis of 54.4 years and a median follow-up time of 5.5 years. In this cohort, the 5-year OS was 69.0, 51.1, and 30.6% for stage IIIA, IIIB, and IIIC, respectively. On propensity score-adjusted multivariate analysis, we found that adjuvant radiation had no statistically significant impact on OS. Furthermore, age older than 60 years, number of nodes, increasing pathologic stage, and absence of immunotherapy correlated with worse OS. In this NCDB analysis, we found that the adjuvant radiotherapy for node-positive, stage III melanoma patients did not improve OS. This is consistent with TROG 02.01; however, there may be patient selection bias not accounted for by the NCDB.

Still waiting for more adjuvant treatment options!!!!  Still.  Waiting. - c