ipi/nivo efficacy in melanoma brain mets, CD8+ T cell actions, and (surprise, surprise!!!) CONCURRENT radiation and immunotherapy is even better in brain mets

I've only said most of this post a zillion times.  Brain mets suck great big hairy green wizard balls!!! We know immunotherapy works in the brain and body.  AND...we KNOW that immunotherapy combined with radiation works even better for brain mets.  But...we begin again...

We'll start with a bit of relatively new information at the cellular level:

Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking. Taggart, Andreou, Scott, et al.  Proc Natl Acad Sci U S A. 2018 Jan 31.

Inhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metastatic tumors that develop within the "immune specialized" brain microenvironment, remain elusive. We established a melanoma tumor transplantation model with intracranial plus extracranial (subcutaneous) tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain. Strikingly, intracranial ICI efficacy was observed only when extracranial tumor was present. Extracranial tumor was also required for ICI-induced increase in CD8⁺ T cells, macrophages, and microglia in brain tumors, and for up-regulation of immune-regulatory genes. Combined PD-1/CTLA-4 blockade had a superior intracranial efficacy over the two monotherapies. Cell depletion studies revealed that NK cells and CD8⁺T cells were required for intracranial anti-PD-1/anti-CTLA-4 efficacy. Rather than enhancing CD8⁺ T cell activation and expansion within intracranial tumors, PD-1/CTLA-4 blockade dramatically (∼14-fold) increased the trafficking of CD8⁺ T cells to the brain. This was mainly through the peripheral expansion of homing-competent effector CD8⁺ T cells and potentially further enhanced through up-regulation of T cell entry receptors intercellular adhesion molecule 1 and vascular adhesion molecule 1 on tumor vasculature. Our study indicates that extracranial activation/release of CD8⁺ T cells from PD-1/CTLA-4 inhibition and potentiation of their recruitment to the brain are paramount to the intracranial anti-PD-1/anti-CTLA-4 activity, suggesting augmentation of these processes as an immune therapy-enhancing strategy in metastatic brain cancer.

OK....so that sounds important and impressive.  Now, there's this, which probably explains a bit of the above:

CD103+ tumor-resident CD8+ T cells are associated with improved survival in immunotherapy naive melanoma patients and expand significantly during anti-PD1 treatment. Edwards, Wilmott, Madore, et al.Clin Cancer Res. 2018 Mar 29.

Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses however, occur in less than half of those treated and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate anti-tumor immune response.  

We performed multi-parameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti-PD-1 therapy.

Increased numbers of CD69+CD103+ tumor-resident CD8+ T cells was associated with improved melanoma-specific survival in immunotherapy-naive melanoma patients. Local IL-15 expression levels strongly correlated with these tumor-resident T cell numbers. The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset and these cells significantly expanded early during anti-PD-1 immunotherapy. 

Conclusions: Tumor-resident CD8+ T cell numbers are more prognostic than total CD8+ T cells in metastatic melanoma. In addition, they are likely to initiate response to anti-PD-1 and anti-LAG-3 treatments. We propose that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade.

Ok.  That is good to know!  Now...how to we make that happen?????

And of course...no melanoma brain met post is complete unless I'm yelling!!!!  So here are a zillion posts about the benefit of immunotherapy COMBINED with radiation for brain mets:

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

And yes...there is this shocking finding!!!  The ipi/nivo combo is better in treating melanoma in the brain than nivo alone!!!  AGAIN!!!  (Just like in the body....sigh....)

Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Long, Atknson, Lo, et al.  Lancet Oncol. 2018 Mar 27.

Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases.

This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy-naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the final survival analysis.

Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8-25), intracranial responses were achieved by 16 (46%) of 35 patients in cohort A, five (20%; 7-41) of 25 in cohort B, and one (6%; 0-30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred.

Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases.

Why in the world the poor folks in Cohort C had to get the shaft TWICE, I don't know!!  Once in being the poor peeps who had already failed a therapy and/or had symptomatic disease and secondly by being given the less effect treatment....DAMN!  Anyhow, as usual, I digress...  So folks with untreated brain mets with no symptoms were put into two groups.  Group A got ipi/nivo and 46% gained a response.  Group B got nivo alone and attained a 20% response rate.  And as noted, the folks with symptoms and/or had already failed one treatment for their brain mets were put into Group C and given nivo only, where they had only 1 response in their n=16.  So...small numbers here...and to me this serves only as reinforcement for what we already know: YES!!!! Immunotherapy works in the brain!!!!  (BUT....even better WITH SRS or gamma knife radiation therapy....circle back to above!!!!)

For what it's worth... - c

SRS and immunotherapy in melanoma brain mets as well as other organs

I have been yelling about the benefits of radiation COMBINED with immunotherapy for soooooooo long!!!  Here are a ZILLION posts!!!!!!!!!!!!!!!!!

Here is a nice review from June of this year:  Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination

While most of the initial data regarding combining radiation WITH immunotherapy started with the good results achieved in folks with brain mets....we are learning more and more about the benefit of the combo in other areas of the body.  Here are two reports:

Efficacy of combined hypo-fractionated radiotherapy and anti-PD-1 monotherapy in difficult-to-treat advanced melanoma patients.  Roger, Finet, Boru, et al. Oncoimmunology. 2018 Mar 13.

Information on the role of radiotherapy in anti-PD-1 monoclonal antibody-treated melanoma patients is limited. We report on a prospective cohort of advanced melanoma patients treated simultaneously with radiotherapy and anti-PD-1 therapy between 01/01/15 and 30/06/16. Tumor evaluations (RECIST 1.1) were performed every 3 months on radiated and non-radiated lesions. Twenty-five advanced melanoma patients (64% AJCC stage IV M1c, 64% on second-line treatment or more, 60% with elevated LDH serum levels) were included. Radiotherapy was performed early (median: 24 days) after the first anti-PD-1 dose in 15 patients with rapidly progressing symptomatic lesion(s) or later (median: 5.4 months) in 10 patients with progressive disease (PD) despite PD-1 blockade. Radiotherapy was limited to one organ in 24 patients and consisted mainly of hypo-fractioned radiotherapy (median dose 26 Gy in 3-5 fractions, 17 patients) or brain radiosurgery (5 patients). Median follow-up after first anti-PD-1 dose was 16.9 m (range 2.7-27.4), with 44% of patients alive at last follow-up. For radiated lesions, rates of complete (CR), partial (PR) responses, stable disease (SD) or PD were 24%, 12%, 24%, and 32%, respectively. For non-radiated lesions, rates of CR, PR, SD, and PD were 20%, 19%, 12%, and 40%, respectively. Responses achieved after radiotherapy for radiated and non-radiated areas were correlated suggesting an abscopal effect. Five patients with CR remained disease-free after discontinuation of anti-PD-1 for a median of 9.5 months. No unusual adverse event was recorded. Hypo-fractionated radiotherapy may enhance efficacy of anti-PD1 therapy in difficult-to-treat patients.

Combined radiotherapy with nivolumab for extracranial metastatic malignant melanoma. Komatsu, Konishi, Aoshima, et al. Jpn J Radiol. 2018 Sep 11.

We retrospectively evaluated the tumor regression after radiotherapy in combination with the immune checkpoint inhibitor nivolumab for metastatic melanoma.  We evaluated the extracranial metastatic melanoma lesions to which concomitant radiotherapy with nivolumab was administered from June 2015 to February 2017. Tumor volume and maximum diameter were measured at the time of pre-radiotherapy and best response, and the tumor reduction rate was assessed in two ways that our hospital adopts: tumor volume and diameter.

Seven lesions in five patients were evaluated. The median time from the start of nivolumab treatment to the start of radiotherapy was 5 months (range 0-22 months). The objective response rate was 85.7% in the evaluation by tumor volume and 42.9% by maximum diameter of the tumor. The objective complete response rate was 28.6% in evaluation by tumor volume and 14.3% by maximum dia. The 1-year tumor control rate was 62.5%. The 1- and 2-year overall survival rate after nivolumab treatment were 75% and 50%, respectively. Two patients who obtained a complete response had presented with vitiligo.

The combination of radiotherapy and nivolumab treatment produced favorable responses. Vitiligo may be correlated with a good response to concomitant radiotherapy with nivolumab.

Good to know.  Immunotherapy WITH radiotherapy WORKS in the brain and body.  Here's one more report confirming the benefit of CONCURRENT administration...

Concurrent versus non-concurrent immune checkpoint inhibition with stereotactic radiosurgery for metastatic brain disease: a systematic review and meta-analysis.  Lu, Goyal, Rovin, et al. J Neurooncol. 2018 Nov 3.

Immune checkpoint inhibition (ICI) is an emerging immunotherapy for metastatic brain disease (MBD). Current management options include stereotactic radiosurgery (SRS), which has been shown to confer prognostic benefit in combination with ICI. However, the effect, if any, of ICI timing on this benefit is currently unclear. The aim of this study was to evaluate the effect of concurrent ICI with SRS on survival outcomes in MBD compared to non-concurrent ICI administered before or after SRS.

Searches of 7 electronic databases from inception to April 2018 were conducted following the appropriate guidelines. 1210 articles were identified for screening. Kaplan Meier estimation of 12-month overall survival (OS), local progression free survival (LPFS) and distant progression free survival (DPFS) were pooled as odd ratios (ORs) and analyzed using the random effects model.  A total of 8 retrospective observational cohort studies satisfied selection criteria.

Compared to non-concurrent ICI, concurrent ICI with SRS conferred a significant 12-month OS benefit, and comparable 12-month LPFS and DPFS. These significances were reflected in the subgroup of melanoma metastases.

Based on the trends of our findings, there appears to exist an optimal time window around SRS of which ICI may confer the most survival benefit. However, current literature is limited by a number of clinical parameters requiring further delineation which limits the certainty of these findings. Larger, prospective, and randomized studies will assist in identifying the time period for which ICI can provide the best outcome in MBD managed with SRS.  

Since ratties put their lives on the line and taught us the benefits of radiation combined with immunotherapy WITHOUT increased side effects (Here's one more report:  CONCURRENT radiation and immunotherapy for brain mets is BEST!!!! (yes, AGAIN!!!)  )....that's what docs are doing, right??????

Stereotactic radiosurgery and immunotherapy in melanoma brain metastases: Patterns of care and treatment outcomes.  Gabani, Fishcher-Valuck, Johanns, et al.
Radiother Oncol. 2018 Jun 27.

Preclinical studies have suggested that radiation therapy (RT) enhances antitumor immune response and can act synergistically when administered with immunotherapy. However, this effect in melanoma brain metastasis is not well studied. We aim to explore the clinical effect of combining RT and immunotherapy in patients with melanoma brain metastasis (MBM).

Patients with MBM between 2011 and 2013 were obtained from the National Cancer Database. Patients who did not have identifiable sites of metastasis and who did not receive RT for the treatment of their MBM were excluded. Patients were separated into cohorts that received immunotherapy versus patients who did not. 

A total of 1104 patients were identified: 912 received RT alone and 192 received RT plus immunotherapy. The median follow-up time was 6.4 (0.1-56.8) months. Patients with extracranial disease (OR 1.603), and patients receiving SRS (OR 1.955) as compared to WBRT, had a higher likelihood of being treated with immunotherapy. The utilization of immunotherapy had nearly doubled between 2011 and 2013 (12.9-22.8%). On multivariable analysis, factors associated with superior OS were younger age, lower medical comorbidities, lack of extracranial disease, and treatment with immunotherapy and SRS. The median OS was 11.1 (8.9-13.4) months in RT plus immunotherapy vs. 6.2 (5.6-6.8) months in RT alone, which remained significant after propensity score matching.  

An increase in trend for the use of immunotherapy was noted, however, an overwhelming majority of the patients with this disease are still treated without immunotherapy. Addition of immunotherapy to RT is associated with improved OS in MBM. Given the selection biases that are inherent in this analysis, prospective trials investigating the combination of RT, especially SRS and immunotherapy are warranted.

Despite overwhelming proof that radiotherapy works best WITH immunotherapy and "is associated with improved Overall Survival in Melanoma Brain Mets", these authors note, "....an overwhelming majority of patients with this disease are still treated without immunotherapy."

WHAT THE HELL?????  WHY??????????????????????????????????

Yep. We know that even when anti-PD-1 is given alone, it works in the brain....  And I've been yelling about this for a while:  ASCO 2018 - Survival of folks having melanoma brain mets with immunotherapy
Now this:

Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial.  Kluger, Chiang, Mahagan, et al.J Clin Oncol. 2018 Nov 8.

Pembrolizumab is active in melanoma, but activity in patients with untreated brain metastasis is less established. We present long-term follow-up of pembrolizumab-treated patients with new or progressing brain metastases treated on a phase II clinical trial.  We enrolled 23 patients with melanoma with one or more asymptomatic, untreated 5- to 20-mm brain metastasis not requiring corticosteroids; 70% of patients had prior systemic therapy. Pembrolizumab was administered for up to 24 months. Brain metastasis response, the primary end point, was assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST). Pretreatment tumors were analyzed for T-cell infiltrate and programmed death ligand 1.  Six patients (26%) had a brain metastasis response. Eight patients (35%) did not reach a protocol evaluation scan and were unevaluable for brain metastasis response as a result of progression or need for radiation. Brain metastasis and systemic responses were concordant, with all ongoing at 24 months. The median progression-free and overall survival times were 2 and 17 months, respectively. Eleven patients (48%) were alive at 24 months. This included three unevaluable patients. One of these three patients had hemorrhaged, and two had symptoms from perilesional edema requiring radiosurgery, but all three patients remained on commercial pembrolizumab more than 24 months later. None of the 24-month survivors received subsequent BRAF inhibitors. Neurologic adverse events occurred in 65% of patients; all adverse events but one were grade 1 or 2. Three patients had seizures, which were treated with anticonvulsants. Most responders had higher pretreatment tumor CD8 cell density and programmed death ligand 1 expression, whereas all nonresponders did not.  Pembrolizumab is active in melanoma brain metastases with acceptable toxicity and durable responses. Multidisciplinary care is required to optimally manage patients with brain metastases, including consideration of radiation to large or symptomatic lesions, which were excluded in this trial. Two-year survival was similar to patients without brain metastasis treated with anti-programmed cell death 1 agents. Concordant brain and extracerebral responses support use of pembrolizumab to treat small, asymptomatic brain metastases.

While this report confirms, again, that anti-PD-1 alone works in the brain, if my mets were treatable through radiotherapy....I would still avail myself of the COMBO!!!  Radiotherapy AND immunotherapy!!!

Then there are the abscopal effects (The situation in which tumors that were NOT irradiated actually respond, shrink, and disappear when distant lesions are treated!!!) that are possible with radiation.  Here's a review: Abscopal responses

Time to abandon single-site irradiation for inducing abscopal effects.  Brooks, Chang.  Nat Rev Clin Oncol. 2018 Nov 6.  

Considerable interest is being directed toward combining immune-checkpoint inhibition (ICI) with radiotherapy to improve response rates to ICI, which have been disappointingly low at around 15-30% among patients with advanced-stage cancers other than melanoma. Since a case report published in 2012, in which authors described the resolution of metastatic disease after irradiation of a single lesion in a patient who had been receiving ICI, hundreds of clinical trials have been launched with the aim of testing the safety and/or efficacy of radiotherapy in combination with immunotherapy, nearly all of which use this single-site irradiation, or 'abscopal', approach. However, emerging preclinical and clinical evidence suggests that this approach likely produces suboptimal results. In this Perspective, we describe this evidence and provide a biological rationale supporting the abandonment of the single-site abscopal approach. We instead advocate exploring comprehensive irradiation of multiple/all lesions in order to enhance the likelihood of obtaining meaningful clinical outcomes - if such a clinical synergy between radiation and ICI does exist - before the failure of the current, single-site approach leads to the potential premature and inappropriate abandonment of radiotherapy in combination with ICI altogether.

Hmmm....  Makes sense to me.  If one irradiated site might produce an abscopal response, it seems that a couple could do better. 

Yep.  Immunotherapy works in the brain.  Yep.  Immunotherapy COMBINED with radiation is a good thing for melanoma patients.  There you go.  Again. - c

ASCO 2017: Hypofractionated radiotherapy with nivo or pembro in melanoma

Y'all know I've been yelling about combining radiation WITH immunotherapy for YEARSSSSS...

Here's a link to about 10 zillion posts:  Radiation and immunotherapy in melanoma

Here, hypofractionated radiotherapy (multiple small doses of radiation) is combined with anti-PD-1 as a single agent ~

Efficacy of combined hypofractionated radiotherapy and anti-PD-1 monotherapy in patients with melanoma.

ASCO 2017. J Clin Oncol 35, 2017. Roger, Finet, Brou, et al.

Background: Information on the role and type of radiotherapy in melanoma pts treated with anti-PD1 is limited. We report a cohort of advanced melanoma pts having received simultaneous hypofractionated radiotherapy and anti-PD-1 monotherapy. Methods: Database search in the prospective database of a referral center with standardized radiotherapy procedures for all pts having received both treatments between 1/1/15-30/6/16. Radiologists performed independent tumor evaluations (RECIST 1.1) every 3 m, both on radiated and non-radiated lesions. Results: 25 pts with inoperable AJCC stage 3-4 melanoma, mean age 60.5 Y. Anti-PD-1 monotherapy was first systemic treatment in only 40% of pts. Median follow-up after onset of anti-PD-1 therapy (83% nivolumab, 17% pembrolizumab) was 13.3 m, with 48% of pts still alive at last follow-up. Radiotherapy was performed either early (within first 3 m of PD-1 blockade) in pts with rapidly progressing symptomatic lesion(s) (60% of pts) or late (greater than 3 months) in pts with slow progression or dissociated response (40% of pts). It consisted of 1 weekly radiation during 4-5 w (84% of pts), or 1 gammaknife radiation for cerebral mets (16% of pts). Median delay between onset of PD-1 blockade and radiotherapy was 1.8 m (range 0.5-11 m). For radiated lesions, rates of complete (CR), partial (PR) responses, stabilization (S) or progression (P) were 24%, 8%, 44%, and 28%, respectively. For non-radiated lesions (84% of pts), rates of CR, PR, S, and P were 29%, 19%, 19%, and 33%, respectively. Among pts radiated late for insufficient response to anti-PD-1 monotherapy, CR or PR in non-radiated lesions (i.e. abscopal response) was observed in 56% of pts. Anti-PD-1 therapy could be discontinued in 4 pts with CR, without relapse to date. No unusual adverse event was recorded. Conclusions: Hypofractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in difficult-to-treat pts. Controlled studies are needed.

25 patients with inoperable Stage 3/4 melanoma.  40% has anti-PD-1 alone as first therapy (83% nivo, 17% pembro).  Radiation was performed either within the first 3 months of anti-PD-1 treatment in patients with rapidly progressing disease (60% of pts) or after three months of therapy in patients with slow progression (40%).  Radiation was 1 weekly session for 4-5 weeks (84% of patients) or one gammaknife treatment for patients with brain mets (16%).
Lesions that were radiated showed:  CR = 24% , PR = 8% , S = 44%, P = 28%. 
Lesions not treated with radiation:    CR = 29%, PR = 19%, S = 19%, P = 33%.
"Among pts radiated late for insufficient response to anti-PD-1 monotherapy, CR or PR in non-radiated lesions (i.e. abscopal response) was observed in 56% of pts."

That abscopal shit be real, y'all!!!! Thanks ratties! - 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

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

Brain mets in melanoma: Don't wait to add anti-PD1 to SRS!!! And....TILs correlates with extent of brain edema and survival time in patients with brain mets

When used alone, radiation does little to help folks with melanoma.  But we've learned that when combined with other therapies....it can make a world of difference!  This post looks at data re: radiation with immunotherapy, intralesional therapy and associated abscopal response:   Radiation and melanoma...a review...    

Here researchers addressed the combination of nivo (Opdivo) and radiation specifically for brain mets:  Nivo/opdivo with radiation better for melanoma patients with brain mets

And now this....reaffirming that both immunotherapy and radiation can be given TOGETHER!!!  Do NOT put off one, to do the other!!!  And...anti-PD1 did better than ipi....

Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery.  Qia, Yu, Kluger, Chiang.  Cancer. 2016 Jun 10.  

Growing evidence suggests that immunotherapy and radiation therapy can be synergistic in the treatment of cancer. This study was performed to determine the effect of the relative timing and type of immune checkpoint therapy on the response of melanoma brain metastases (BrMets) to treatment with stereotactic radiosurgery (SRS).  Seventy-five melanoma patients with 566 BrMets were treated with both SRS and immune checkpoint therapy between 2007 and 2015 at a single institution. Immunotherapy and radiosurgery treatment of any single lesion were considered concurrent if SRS was administered within 4 weeks of immunotherapy. [After statistical analysis...]  Concurrent use of immunotherapy and SRS resulted in a significantly greater median percent reduction in the lesion volume at 1.5, 3, and 6 months in comparison with nonconcurrent therapy. The median percent reduction in the lesion volume was also significantly greater for anti-programmed cell death protein 1 (anti-PD-1) than anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) at 1.5, 3, and 6 months.  The administration of immunotherapy within 4 weeks of SRS results in an improved lesional response of melanoma BrMets in comparison with treatment separated by longer than 4 weeks. Anti-PD-1 therapy also results in a greater lesional response than anti-CTLA-4 after SRS.


And while this is a bit old....it does describe the phenomenon that both causes edema in brain mets as well as survival....

Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases.  Berghoff, Fuchs, Ricken, et al.  Oncoimmunology. 2015 Jun 9.  

The immune microenvironment of the brain differs from that of other organs and the role of tumor-infiltrating lymphocytes (TILs) in brain metastases (BM), one of the most common and devastating complication of cancer, is unclear. We investigated TIL subsets and their prognostic impact in 116 BM specimens using immunohistochemistry for CD3, CD8, CD45RO, FOXP3, PD1 and PD-L1. The Immunoscore was calculated as published previously. Overall, we found TIL infiltration in 115/116 (99.1%) BM specimens. PD-L1 expression was evident in 19/67 (28.4%) BM specimens and showed no correlation with TIL density. TIL density was not associated with corticosteroid administration. A significant difference in infiltration density according to TIL subtype was present; high infiltration was most frequently observed for CD3+ TILs (95/116; 81.9%) and least frequently for PD1+ TILs (18/116; 15.5%). Highest TIL density was observed in melanoma, followed by renal cell cancer and lung cancer BM (p < 0.001). The density of CD8⁺ TILs correlated positively with the extent of peritumoral edema seen on pre-operative magnetic resonance imaging. The density of CD3+ (15 vs. 6 mo), CD8⁺ (15 vs. 11 mo) and CD45RO+ TILs (18 vs. 8 mo) showed a positive correlation with favorable median OS times. Immunoscore showed significant correlation with survival prognosis (27 vs. 10 mo). The prognostic impact of Immunoscore was independent from established prognostic parameters at multivariable analysis (HR 0.612). In conclusion, our data indicate that dense TILs infiltrates are common in BM and correlate with the amount of peritumoral brain edema and survival prognosis, thus identifying the immune system as potential biomarker for cancer patients with CNS affection. Further studies are needed to substantiate our findings.

Brain mets suck great big, green, hairy, wizard balls!!!  But...there's hope.  Hang in there!  - c

ASCO 2017: Melanoma brain mets

Melanoma sucks great big green hairy wizard balls!  And when you add brain mets, you really have a pair!!!!  I have been yelling about treatments for brain mets for so long that I feel like Paula Poundstone, "I started writing because banging my head against the wall was starting to chip the paint!"  I wrote this post in 2014: Should melanoma brain met patients be allowed in clinical trials?
Along with this one:  Anti-PD1 in melanoma: T-cells, the brain, and EVERYWHERE ELSE!!!!
And this in 2015:  Yep! Immunotherapy can work in the brain

For far too long, folks with brain mets (and don't even think about leptomeningeal disease) have been EXCLUDED from participation in clinical trials!!!  Why????  You can keep them in their own arms... Pharma CEO Person!!!

Finally this study opened:  ASCO 2015: New trial for melanoma brain mets!!! Ipi and Nivo, followed by Nivo alone (CheckMate 204)  (Wait til you see what's below!!!)

First up:  Nivo alone vs ipi/nivo in folks with brain mets.... (hmmmmm...let me think.....):

A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC).

2017 ASCO. J Clin Oncol 35, 2017. Long, Atkinson, Menzies, et al.

Background: Nivolumab (nivo) and the combination of nivo + ipilimumab (ipi) improve response rates (RR) and progression-free survival (PFS) compared with ipi alone in clinical trials of metastatic melanoma pts, but pts with untreated brain mets were excluded. [No SHIT!!!  And how many times have I yelled about this??????]   Brain mets are a major cause of morbidity and mortality in melanoma and their management is critical. We sought to determine the antitumour activity and safety of nivo and nivo+ipi in pts with active melanoma brain mets. Methods: This open-label, ph II trial enrolled 3 cohorts of pts naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014 - Feb 2017. Pts with asymptomatic melanoma brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3W x4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets 1) that failed local therapy (new +/- progressed in previously treated met), 2) were neurologically symptomatic and/or 3) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) greater than/= to wk12. Secondary endpoints were best extracranial response (ECR), best overall response (OR), IC PFS, EC PFS, overall PFS, OS, and safety. Results: A total of 66 pts (med f/u 14 mo) were included in this analysis of total 76 planned; median age 60y, 77% male. For cohorts A, B and C: elevated LDH 48%, 58% and 19%; V600BRAF 44%, 56% and 81%; prior BRAFi 24%, 24%, 75%. Table shows RR, PFS and OS. ICR in cohort A treatment naïve vs prior BRAFi was 53% vs 16%. Treatment-related gd 3/4 toxicity in cohorts A, B and C were 68%, 40% and 56%, respectively. There were no treatment-related deaths. Conclusions:  Nivo monotherapy and ipi+nivo and are active in melanoma brain mets. Ipi+nivo had reduced activity in pts who progressed on BRAFi. Pts with symptomatic brain mets, leptomeningeal mets or previous local therapy responded poorly to nivo alone. 

	A, ipi/nivo (n=25)	B, nivo (n=25)	C, nivo (n=16)
ICR %	44 (24, 65)	20 (7, 41)	6 (0, 30)
ICR (complete response)	16 (24, 65)	12 (7, 41)	0
ECR %	38 (18, 62)	26 (10, 48)	21 (5, 50)
6 Month PFS %	50 (33, 75)	29 (15, 50)	0
6 Month OS %	76 (59, 97)	59 (41, 86)	44 (25, 76)

So....in this report (using only treatment naive and asymptomatic patients)...not surprisingly...the ipi/nivo combo did best in treating folks with melanoma brain mets...as it does in melanoma patients' mets located elsewhere!

Remember the ASCO 2015 link above?  Here are the results of THAT ipi/nivo study:

Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204.

ASCO 2017. J Clin Oncol 35, 2017. Tawbi, Forsyth, Algazi, Hamid, Hodi, ...Postow, ….et al.

Background: Brain metastases (BMts) are a major cause of morbidity/death in MEL. We report the first efficacy data in MEL patients (pts) with BMts who received NIVO+IPI in study CheckMate 204. Methods: In this multicenter US trial, MEL pts with greater than/ = to 1 measurable BMt 0.5-3.0 cm and no neurologic symptoms or steroid Rx received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until progression or toxicity. Pts with severe adverse events (AEs) during NIVO+IPI could receive NIVO when toxicity resolved; stereotactic radiotherapy (SRT) was allowed for brain oligo-progression if an assessable BMt remained. The primary endpoint was intracranial (IC) clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] for greater than or = to 6 months). The planned 90-pt accrual is complete; we report efficacy and updated safety for 75 pts with disease assessment before the Nov 2016 database lock. Results: Median age was 59 yrs (range 22–79). Median number of induction doses was 3; 26 pts (35%) received 4 NIVO+IPI doses and 38 pts (51%) began NIVO maintenance. Response data are reported at a median follow-up of 6.3 months. The IC objective response rate (ORR) was 56%; 19% of pts had a complete response. IC and extracranial responses were largely concordant. Rx-related grade 3/4 AEs occurred in 48% of pts, 8% neurologic, including headache and syncope. Only 3 pts (4%) stopped Rx for Rx-related neurologic AEs. One pt died of immune-related myocarditis. Conclusions: In CheckMate 204, prospectively designed to investigate NIVO+IPI in MEL pts with BMts, NIVO+IPI had high IC antitumor activity with objective responses in 56% of pts, CR in 19%, and no unexpected neurologic safety signals. The favorable safety and high anti-melanoma activity of NIVO+IPI may represent a new Rx paradigm for pts with asymptomatic MEL BMts and could change practice to avoid or delay whole brain RT or SRT. 

	global	intracranial	extracranial
Best overall response, n (%, 95% CI)
CR	2 (3, 0-9)	14 (19, 11-29)	4 (5, 1-13)
PR	40 (53, 41-65)	28 (36, 26-49)	33 (44, 33-56)
SD greater than 6 mo	5 (7, 2015)	6 (8, 3-17)	2 (3, 0-9)
ORR, n (%, 95% CI)	42 (56, 44-68)	42 (56, 44-68)	37 (49, 38-61)

Again we are looking at the results of the cream of the melanoma brain met crop: folks who are asymptomatic. Nevertheless, the report above makes it very clear that immunotherapy (specifically ipi/nivo in this case) works in the brain and the body, with 56% of patients attaining an intracranial objective response, 19% of patients attaining a complete response, with responses to head and body being proportional.  Side effects were sadly as expected.  And while response was attained using immunotherapy only (ie with NO radiation), I'm not sure that, "The favorable safety and high anti-melanoma activity of NIVO+IPI may represent a new Rx paradigm for pts with asymptomatic MEL BMts and could change practice to avoid or delay whole brain RT or SRT"  is a conclusion that can be so readily drawn.  (Especially since they just randomly throw in "whole brain RT"...something we KNOW provides no real benefit in melanoma and is used only in the most extreme cases.)

I am an odd duck in many ways. However, I (and my brain mets) have sat on both sides of this fence.  I had one brain met treated with SRS (stereotactic radiation) in April of 2010.  Before I could gain access to treatment, I developed another. Still, I was accepted into my Nivo trial, getting my first dose in December of 2010.  By the next set of scans, three months later, the met was gone...and this was without additional radiation and nivo only, at a dose of 1mg/kg.  Still....given the preponderance of the evidence, I would be hard pressed to choose to forego SRS should I develop another brain met..... 

Here are just a few reports: 
2015 - Why immunotherapy is good for lots of folks...not just those with melanoma and how radiotherapy may make it even better!

2016 - Nivo (Opdivo) with radiation = better for melanoma patients with brain mets

2016 - One more time....better responses when radiation is combined with immunotherapy

2016 - Brain mets in melanoma: Don't wait to add anti-PD1 to SRS!!! And....TILs correlates with extent of brain edema and survival time in patients with brain mets

2016 - Radiation and ipi = better responses than either alone!!! (AGAIN!!!)

2017 - SRS (radiation) better WITH ipi (immunotherapy) rather than AFTER in melanoma generally, and brain mets specifically

2017 - Efficacy of Pembro (Keytruda) in melanoma brain mets

2017 - Immunotherapy with SRS does NOT increase risk of radiation necrosis in melanoma brain mets!!!

Not to beat a "dead brain met" or anything...  I believe in moving with the times and evidence based practice.  IF we can attain an equivalent response by treating brain mets with ONLY immunotherapy as we can when immunotherapy is combined with radiotherapy...then I am all for it!!!!  However, the links above provide a great deal of data comparing results when we treat melanoma mets with and without radiation be it SRS or gamma knife.

Now, here's this (GKRS is gamma knife radiation and is basically equivalent to SRS, stereotactic radiation): 

Outcomes of melanoma brain metastases treated with stereotactic radiosurgery with and without concurrent immune checkpoint therapy.

ASCO 2017. J Clin Oncol 35, 2017. Yang, Cercle, Yaeh, et al.  

Background: Evidence supports a synergistic effect between immunotherapy and radiotherapy. [Yep!!!]  In this single-institution study, we compared outcomes of patients (pts) with melanoma brain metastases (BMs) who received Gamma Knife Radiosurgery (GKRS) with and without concurrent immune checkpoint blockade (ICB). Methods: Using an IRB-approved protocol, we identified pts with melanoma BMs who received GKRS from 5/2000 to 8/2016. Treatment was deemed concurrent if patients had GKRS within 4 weeks of ICB. Irradiated lesion control, tumor growth rate (TGR; percent change in product diameters per month), distant brain control, overall response rate (ORR) by modified WHO criteria, best response, and overall survival (OS) were compared. Results: 28 pts were identified: 17 (34 BMs total) received GKRS alone; 11 (23 BMs total) received concurrent GKRS/ICB. ICB included: ipilimumab (n = 3), anti-programmed death-1 (anti-PD-1) therapy (n = 4), and combined ipilimumab + nivolumab (n = 4). In comparing baseline characteristics between the GKRS alone and GKRS/ICB groups: median age was 65 v. 59 years, proportion of males was 53% v. 73%, 41% v. 45% had prior neurosurgery, and median number of prior systemic therapies was 1 v. 0. There was no difference in irradiated lesion control (6-month control rate 86% v. 96%; n = 57, median TGR (-14% [range -100% to +61%] v. -20% [range -71% to 0%]; n = 42 lesions), or distant brain control (6-month control rate 68% v. 60%; median follow-up 8.6 months v. 8.0 months) with GKRS/ICB v. GKRS alone. The ORR with GKRS alone v. GKRS/ICB was 61% v. 47%, and the median maximum reduction in BM bidimensional measurement was -69% v. -45%. Median OS from the date of GKRS was not reached for the GKRS/ICB group and was 16.6 months for the GKRS alone group. Conclusions: There was no difference in local lesion control, TGR, or distant brain control with concurrent GKRS/ICB compared to GKRS alone, but the study was limited by small patient numbers and biased by closer follow-up in the GKRS/ICB group. OS was longer with concurrent ICB, likely reflecting the survival improvement with immune checkpoint inhibitors.  

These were not your pristine, 'Oops I have a brain met, who knew?', ratties. Most of these had already been in the trenches with prior neurosurgery and systemic therapy.  That being said, there was no difference in local control when radiation was given alone as compared to when it was given with immunotherapy.  However, overall survival median was not yet reached in those who got immunotherapy WITH radiation, but was only 16.6 months for those with radiation alone. The last sentence may well speak volumes. 

Finally, there's the BRAF/MEK inhibitors...which work on brain mets, too!!!

COMBI-MB: A phase II study of combination dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600–mutant (mut) melanoma brain metastases (MBM).

ASCO 2017. J Clin Oncol 35, 2017. Davies, Robert, Long, ….Flaherty, et al.

Background: CNS metastases are common and associated with very poor prognosis in pts with metastatic melanoma (MM). In the phase II BREAK-MB trial, D had clinical activity in BRAF V600–mut MBM. D + T has shown superiority over D alone in pts with BRAF V600–mut mm without MBM; however, efficacy of this regimen on MBM has not been characterized. Here, we report results from a phase II trial of D + T in BRAFV600–mut MBM (COMBI-MB). Methods: This open-label, phase II study evaluated D 150 mg BID + T 2 mg QD (Dabrafenib and trametinib) in 4 MBM cohorts: (A) BRAFV600E, asymptomatic MBM, no prior local treatment (Tx); (B) BRAFV600E, asymptomatic MBM, prior local Tx; (C) BRAFV600D/K/R, asymptomatic MBM, with or without prior local Tx; and (D) BRAFV600D/E/K/R, symptomatic MBM, with or without prior local Tx. The primary objective was intracranial response rate (IRR) in cohort A (null hypothesis, IRR less than/= to 35%). Secondary endpoints included IRR in cohorts B, C, and D; extracranial (ERR) and overall (ORR) response rates; intracranial (IDCR), extracranial (EDCR), and overall (ODCR) disease control rates; duration of IR, ER, and OR; PFS; OS; and safety. Results: 125 pts were enrolled (A, n = 76; B, n = 16; C, n = 16; D, n = 17). In cohort A, median age was 52, 53% were male, and 37% had LDH greater than ULN. At data cutoff (28 Nov 2016; median f/u, 9.0 mo), in cohort A, investigator-assessed IRR was 58% (IDCR, 78%), ERR was 55% (EDCR, 80%), and ORR was 58% (ODCR, 80%). Median duration of IR, ER, and OR was 6.5 mo, 10.2 mo, and 6.5 mo, respectively. Median PFS was 5.6 mo. Independent review supported these results. 6-mo OS was 79%; with 31 pts (41%) still in f/u, preliminary median OS was 10.8 mo. Efficacy in cohorts B, C, and D will be reported. AEs across cohorts (any, 98%; grade 3/4, 48%) were consistent with prior D + T studies; 10% of pts (8% in cohort A) discontinued due to AEs. Conclusions: In this first report of a phase II trial evaluating a BRAF and MEK inhibitor combination in BRAFV600–mut MBM, the primary endpoint was met. Promising IRR and IDCR were seen with D + T, but responses appear less durable than reported for mm without MBMs. No unexpected safety issues were observed. 

Again, no real news here.  BRAF/MEK inibitor combo's work in brain mets...much like they work in the body of those who are BRAF +, but responses are not durable.  However, when utilized strategically, they are an important part of our arsenal against melanoma.

I hope I have been able to share some needed information and made what is hard to wrap ones head around (I crack myself up!!!), a little more comprehensible.  However, at this point, my holy head is tired.  I think I'll go make a cute pink Polly top!!!  That should get a girl back on track!

Love and thanks to all the ratties.  We would know even less if it were not for you! - c

LATE NOTE:  The Edster found this video interview in which Dr. Long breaks down some of the data above:  Dr. Long talks brain mets as well as Dabrafenib and trametinib
Thanks, Ed!  You can look back to a discussion of dabrafenib and trametinib outcomes in a post from December 2016 if you're interested.  For what it's worth! - c