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

Abscopal Effects of radiotherapy on melanoma...more info...

Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy.  Grimaldi, et al.  Oncoimmunology.  2014, May.  Synopsis:

...'the "abscopal effect" is the regression of non-irradiated metastatic lesions distant from the primary tumor site directly subjected to radiation.  This response is rare, but is thought to be an immune-mediated phenomenon, suggesting that if RT and immunotherapy were combined the effect could be enhanced.  In this study, patients were treated with ipi followed by radiation in an expanded access program in Italy.  Those who progressed on ipi (21) qualified. 13 patients received RT for brain mets, 8 were given RT at extracranial sites.  An abscopal response was observed in 11 patients (52%).  Median time from RT to abscopal response was one month.  Median overall survival for all 21 patients was 13 months (range 6-26).  Median OS for patients with abscopal response was 22.4 months (range 2.5-50.3) vs 8.3 months without the response.  A local response to RT was detected in 13 patients, and of those, 11 patients (85%) had an abscopal response and abscopal effects were noted ONLY in patients exhibiting local response.'

The authors recommend additional trials with greater numbers to validate these results...and I say, "Go for it!!!"  Not just in studies, but here in the US these are treatment measures that oncs can already provide!!!  Best - c

Ipi and radiation...a good combo for melanoma mets...brain and otherwise!!!

We've been hearing more and more about this!  Here are two new articles...

Ipilimumab and radiation therapy for melanoma brain metastasis. 
Silk, Bassetti, West, Tsien, Lao.  Cancer Med. 2013 December.

Ipilimumab, an antibody that enhances T-cell activation, may augment immunogenicity of tumor cells that are injured by radiation therapy.  We hypothesized that patients with melanoma brain metastasis treated with both ipi and radiotherapy would have improved overall survival, and that the sequence of treatments may affect disease control in the brain.  We analyzed the clinical and radiographic records of melanoma patients with brain mets who were treated with whole brain radiation therapy or stereotactic radiosurgery between 2005 and 2012. ...Several patients were identified, 33 of whom received ipi and 37 who did not.  The patients who received ipi had a...median survival of 18.3 months, compared with 5.3 months for patients who did not received ipi.  Ipi and stereotactic radiosurgery were each significant predictors of improved overall survival.  Four of 10 evaluable patients (40%) who received ipi prior to radiotherapy demonstrated a partial response to radiotherapy, compared with two of 22 evaluable patients (9.1%) who did not received ipi.  Ipi is associated with a significantly reduced risk of death in patients with melanoma brain mets who underwent radiotherapy, and this finding supports the need for mulimodality therapy to optimize patient outcomes.

So...40% of patients with melanoma brain mets who had ipi then radiation showed a partial response.  While only 9% of patients treated only with radiotherapy (no ipi) showed the same response.  The numbers of patients in this review are small and wonky...but this effect is showing up more and more as talking points when the melanoma big dogs are interviewed and in the literature.

Combined ipi and radiotherapy for metastatic melanoma.
Menzel, Abendroth, Kashani-Sabet, Minor. Center for Melanoma Research and Treatment, California Pacific Medical Center, San Francisco. International Journal of Radiation Oncology.  October 2013.

The efficacy and toxicity of ipi when combined with radiotherapy (RT) is unclear, though an abscopal effect has recently been reported in multiple patients receiving ipi and subsequent RT. This is our retrospective experience...
Methods:  Melanoma patients treated with ipi and subsequent RT...NON-cranial lesions were identified.  All patients had CT scans within 1 and 3 months of RT initiation and conclusion respectively....
Results:  Ten patients with median age of 65 years received RT via a linear accelerator of CyberKnife...Median number of lesions irradiated lesions was 1 (range = 1-3).  Patients received ipi (3mg/kg, 3-4 doses every 6 months) for a median of 11.9 months pre-RT.  Eight patients had progressive disease, two had stable disease at RT initiation.  At a median follow-up of 12+ months, median progression free survival and overall survival have not been reached.  At last follow-up, 2 patients had complete responses, 4 had partial responses, 1 had stable disease, and 3 had progressive disease.  All irradiated lesions were controlled.  There was one death related to brain mets.  Among 5 patients evaluated for abscopal effect, 2 had progressive disease out of field, 1 had stable disease out of field, and 2 evidenced abscopal effect, with regression or clearance of non-irradiated lesions.
CONCLUSIONS:  Combined ipi and RT is a treatment option in metastatic melanoma with apparently little additive toxicity when hypofractionated RT is employed.  The abscopal effect is an increasingly common phenomenon in observed patients treated with this regimen.

So....Still small numbers...and still sucky results for many...but better than ipi or radiation alone for others!!!  After getting ipi....8 patients had progressive disease and 2 had stable disease.  BUT...after getting RT, 12+ months out - 2 have had a complete response, 4 have had partial responses, 1 has stable disease, and 3 have progressive disease with one death.  Still better than the 8 with progressive disease after ipi alone!!!  Per my Bentie statistician that is a clinical benefit of 70%!!!!  Then there is the abscopal effect to consider, with, of the 5 patients evaluated for it, 2 demonstrating progressive disease out of the field of radiation, 1 with stable tumors out of the field, and 2 with a positive abscopal effect with tumors regressed or cleared in non-radiated areas!  I think we are still unclear if ipi followed by RT is best...or vice versa...or if it matters at all.  I know there are more studies looking at this ongoing.

Fingers crossed for all of you out there!!! - 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

Report on intratumoral IL-2 with intratumoral ipi for nonresectable Stage III/IV melanoma

I first reported on this treatment in this link from ASCO 2015:

ASCO 2015: Intralesional therapy for melanoma

Within, among other reports, there is this:

A phase 1 study of intratumoral injection of ipilimumab and interleukin-2 in patients with unresectable stage III-IV melanoma.  ASCO - J Clin Oncol 33, 2015.  Bowen, Meek, Williams, Grossman, et al.

Intratumoral IL-2 is highly effective and well tolerated, but does not generate systemic immunity or response in untreated lesions.  IV ipi lowers the threshold for T cell activation leading to a durable clinical response in a minority of melanoma patients, but is associated with potentially severe toxicities.  Since IV ipi doesn't have tissue distribution, circulating anti-tumor T cells activated by the drug may differ greatly from tumor infiltrating lymphocytes activated by INTRATUMORAL ipi in terms of quantity and quality.  Therefore, we hypothesized that a combination of IT IL-2 and IT ipi would effectively hyperactivate and expand TILs to engender systemic immunity with minimal toxicity.   This phase 1 dose escalation trial for ipi and fixed dose IL-2 involved patients with unresectable stage III/IV melanoma and at least one injectable lesions.  A single lesion in each patient was treated with IL-2 IT TIW for 2 wks, then BIW for 6 wks, with escalating doses of ipi IT weekly for 8 weeks.  RESULTS:  12 patients were treated with 3 ipi dose levels.  Treatments were well tolerated.  The only grade 3 toxicity was injection site/tumor necrosis, not dose limiting.  Other toxicities were grade 1.  An abscopal effect (response in a least 1 NON-injected lesion) was seen in 9/12 patients (75%).  10 patients were evaluable for immune response:  4 with partial regression (40%) and 6 had progressive disease, though later one PD was later found to be a complete response by resection.  The 2 nonevaluable patients had regression of multiple skin lesions.  An increase in the frequency of IFN producing CD8+ T cell was detected in 6/8 abscopal responders.  Tbet+ and granzyme B+ CD8+ T cells were observed in 4/5 and 3/5 responders tested, respectively.  Researchers plan to conduct a phase II trial using IT Ipi/IL-2 in conjunction with systemic immunotherapy.

Above, these researchers state that they are planning to conduct a phase II trial with this treatment process, possibly combined with systemic therapy...but this (below) was recently published:  (I left all author names so you can note the researchers.)

A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma.  Ray, Williams, Meek, Bowen, Grossmann, Andtbacka, Bowles, Hyngstrom, Leachman, Grossman, Bowen, Holmen, VanBrocklin, Suneja, Khong.  Oncotarget. 2016 Jul 6.

Intratumoral interleukin-2 (IL-2) is effective but does not generate systemic immunity. Intravenous ipilimumab produces durable clinical response in a minority of patients, with potentially severe toxicities. Circulating anti-tumor T cells activated by ipilimumab may differ greatly from tumor-infiltrating lymphocytes activated by intratumoral ipilimumab in phenotypes and functionality. The objective of this study was to primarily assess the safety of intratumoral ipilimumab/IL-2 combination and to obtain data on clinical efficacy.

There was no dose limiting toxicity. While local response of injected lesions was observed in 67% patients, an abscopal response was seen in 89%. The overall response rate and clinical benefit rate by immune-related response criteria (irRC) was 40% and 50%, respectively. Enhanced systemic immune response was observed in most patients and correlated with clinical responses.

Twelve patients with unresectable stages III/IV melanoma were enrolled. A standard 3+3 design was employed to assess highest tolerable intratumoral dose of ipilimumab and IL-2 based on toxicity during the first three weeks. Escalated doses of ipilimumab was injected into only one lesion weekly for eight weeks in cohorts of three patients. A fixed dose of IL-2 was injected three times a week into the same lesion for two weeks, followed by two times a week for six weeks.

Intratumoral injection with the combination of ipilimumab/IL-2 is well tolerated and generates responses in both injected and non-injected lesions in the majority of patients.

So...this appears to be the same 12 patients originally reported on....perhaps with a bit more information upon follow-up...with the abscopal response rate being reported at 89% vs the 75% noted in the earlier report.  Or maybe they just needed to have one more article published for their advancement in academia?  Who knows?  Still looks promising.  Don't know why they haven't done a phase II study.  Though I did find this....a phase II study conducted in Germany with no results publishes as of July 6:  clinicaltrials.gov - intratumoral ipilimumab and interleukin 2

If I find any more intel, I'll let you know!  For what it's worth. - 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

Radiation and immunotherapy...not just safe together...but better!!! (AGAIN!!!)

I keep saying it!!!  Here's a link to lots of data (and my rants)!!!!

radiation and immunotherapy

Now this:

Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy: a safe and effective combination.  Aboudaram, Modesto, Chaltiel, et al.  Melanoma Res. 2017 Aug 28.

A combination of immune-checkpoint inhibitors and radiation therapy (RT) represents a promising therapeutic strategy in part mediated by the abscopal effect, but clinical experience related to this combination remains scarce. Clinical data and patterns of treatment were retrospectively collected from all consecutive patients with metastatic melanoma and receiving programmed-death 1 (PD-1) immune-checkpoint inhibitors. Survival data, best overall response, and acute and delayed toxicities were compared between patients receiving concurrent RT (IR) or no irradiation (NIR). Fifty-nine patients received anti-PD-1 immunotherapy [pembrolizumab (n=28) or nivolumab (n=31)] between August 2014 and December 2015 at our institution. Among these, 29% (n=17) received palliative RT for a total of 21 sites, with a mean dose of 30 Gy delivered in 10 fractions. Acute and late toxicity profiles were similar in the two groups. After a 10-month median follow-up, the objective response rate (complete or partial response) was significantly higher in the IR group versus the NIR group (64.7 vs. 33.3%) and one complete responder after RT was compatible with an abscopal effect. The 6-month disease-free survival and overall survival rates for the NIR group versus the IR group were 49.7 versus 64.7% and 58.8 versus 76.4%, respectively. We report here that the combination of RT and anti-PD-1 immunotherapy is well tolerated and leads to a significant higher tumor response rate within and outside the irradiated field, which is emphasized by the first reported case of an abscopal effect in solid tumors.

Now....we already know that anti-PD-1 gains better responses with fewer side effects both in the brain and body than ipi.  But there is even this...in regard to ipi combined with radiation:

Stereotactic Radiosurgery and Ipilimumab Versus Stereotactic Radiosurgery Alone in Melanoma Brain Metastases. Nruyen, Castreljon, Vaidis, Johnson.  Cureus. 2017 Jul 25.  

Benefits of stereotactic radiosurgery (SRS) have been well established in melanoma brain metastases (MBM). Immunotherapy agents such as ipilimumab (ipi) have recently demonstrated clinical efficacy in advanced disease as well. The theoretical synergistic effects of combining these therapies in MBM have not been explored in detail, however, we conducted a systematic review with meta-analysis of studies that compared combined SRS and ipi versus SRS alone in MBM. Medical Literature Analysis and Retrieval System Online (MEDLINE) and Central databases were used for our literature search, which was conducted by three reviewers. We included studies that examined SRS and ipilimumab compared to SRS alone in MBM. Pertinent results were tabulated in a standardized spreadsheet. Newcastle-Ottawa Scale (NOS) Risk of Bias Assessment and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method for rating evidence quality were used for qualitative analysis. Review Manager was used for statistical analysis. We identified four cohort studies that compared SRS plus ipi versus SRS alone in MBM. As per the GRADE criteria, we found low-quality evidence for survival benefits associated with combined treatment. Meta-analysis confirmed a significant benefit in survival for SRS and ipilimumab. There were no significant differences between comparison groups for local control, distant brain control, radiation necrosis, or intracranial bleeding. We conclude that low-quality evidence exists for superior overall survival in MBM treated with SRS and ipilimumab compared to SRS without ipilimumab. There is also no increased risk of radiation necrosis and/or intracranial bleeding with combining radiation and immunotherapy in this setting.

If your doc tells you that he can't administer immunotherapy WITH radiation...that some delay is needed between the two...or some other tommy rot  ~  Print and read aloud to him or her...this...or any of the other MANY research articles noted in the link above!!!

Whew!!!  Someday I'm gonna get to quit yell'n!!!  - c

ASCO 2015 - intralesional therapy for melanoma

I've been reviewing articles that have come out of ASCO the past couple of weeks.  Here is my round up of those related to intralesional therapy.

A multicenter, open-label trial of talimogene laherparepvec (T-VEC) plus pembrolizumab vs pembrolizumab monotherapy in previously untreated, unresected, stage IIIB-IV melanoma.  ASCO - J Clin Oncol 33, 2015.  Ribas, Puzanov, Gajewski, et al.

T-VEC is a herpes simplex virus-1-based oncolytic immunotherapy designed to preferentially replicate tumors, produce GM-CSF and stimulate an anti-tumor immune response.  {Remember this definition from a prior post:  GM-CSF can be given to premature babies and leukemia patients with low white cell counts to help build them back up....and reverse immune suppression.}  OPTiM, a phase III trial of T-VEC vs GM-CSF in unresected stage IIIB-IV melanoma (n=436), ....had improved durable response rate in the T-VEC arm (16 vs 2%).  Pembrolizumab is a human programmed death receptor-1 (PD-1) blocking antibody [anti-PD1 product, Keytruda] FDA approved in US for patients with unresectable or metastatic melanoma [after failing ipi and if BRAF V600 positive, BRAF inhibitors as well].  
     In this study, started Dec 2014, T-VEC is injected into cutaneous, subcutaneous or nodal lesions at up to 4 ml on day 1, then up to 4 ml on day 22 and every 2 weeks  (phases 1B and 2).  Pembro is given at 200 mg IV every 2 weeks from day 36 in phase 1B (n=20) and day 1 in phase 2 (n=90).  Treatment with both therapies will be given (whichever comes first) until: complete response or progression of disease, intolerance, for up to 2 years.  T-VEC injections stop when there are no longer injectable lesions. Patients in Phase 2 will be randomized 1:1 to T-VEC and pembro vs pembro alone.

Tumor size and clinical outcomes in melanoma patients treated with T-VEC. ASCO - J Clin Oncol 33. Kaufman, Amatruda, Nemunaitis, et al.

436 patients.  Previously treated and untreated.  Stage IIIB-IV mel in OPTiM, randomized 2:1 phase 3 trial of IT T-VEC vs subq GM-CSF.  288 T-VEC and 126 GM-CSF patients.  Median calculation for size of tumor at baseline was 14.8cm squared for T-VEC and 14.1 for GM-CSF.  Median size was higher with advanced stage.  Results for this study:  T-VEC patients, patients with lower than median sized tumors and lower stage were associated with better overall survival.

Survival, safety, and response patterns in a phase 1b multicenter trial of talimogene laherparepvec (T-VEC) and ipi in previously untreated, unresected stage IIIB-IV melanoma.  ASCO - J Clin Oncol 33, 2015.  Puzanoz, Milhem, Hamid, Kaufman, et al.

History on T-VEC as noted above.  Requirements:  Stage IIIB-IV melanoma patients with no prior systemic treatment, measurable disease and at least 1 injectable cutaneous, sub q, or nodal lesion.  T-VEC was given IT at week 1, week 4, and every 2 weeks until injectable tumor was gone or disease progression.  Ipi was given at 3mg/kg every 3 wks for 4 infusions starting week 6.  RESULTS:  At cutoff, all patients were 17 months from start of treatment.  18 patients were treated.  Grade 3/4 AE's occurred in 32% and grade 3/4 immune related AE's occurred in 2 patients with no treatment-related deaths.  Overall response rate was 56% (33% complete response) and DRR was 44%.  Median time to response was 5.3 months.  Median progression free survival was 10.6 months.  Median overall survival was not reached.  12 month and 18 month survival were 72% and 67%.  On a lesion level, 24 and 11 of 35 indexed lesions and 8 and 5 of 16 uninjected lesions regressed at least 50%  and 100%, respectively.  Conclusion:  At more than 17 months out, T-VEC + ipi continued to demonstrate durable response with 2/3 patients alive at 18 months and no new safety signals.
 

A phase 1 study of intratumoral injection of ipilimumab and interleukin-2 in patients with unresectable stage III-IV melanoma.  ASCO - J Clin Oncol 33, 2015.  Bowen, Meek, Williams, Grossman, et al.

Intratumoral IL-2 is highly effective and well tolerated, but does not generate systemic immunity or response in untreated lesions.  IV ipi lowers the threshold for T cell activation leading to a durable clinical response in a minority of melanoma patients, but is associated with potentially severe toxicities.  Since IV ipi doesn't have tissue distribution, circulating anti-tumor T cells activated by the drug may differ greatly from tumor infiltrating lymphocytes activated by INTRATUMORAL ipi in terms of quantity and quality.  Therefore, we hypothesized that a combination of IT IL-2 and IT ipi would effectively hyperactivate and expand TILs to engender systemic immunity with minimal toxicity.   This phase 1 dose escalation trial for ipi and fixed dose IL-2 involved patients with unresectable stage III/IV melanoma and at least one injectable lesions.  A single lesion in each patient was treated with IL-2 IT TIW for 2 wks, then BIW for 6 wks, with escalating doses of ipi IT weekly for 8 weeks.  RESULTS:  12 patients were treated with 3 ipi dose levels.  Treatments were well tolerated.  The only grade 3 toxicity was injection site/tumor necrosis, not dose limiting.  Other toxicities were grade 1.  An abscopal effect (response in a least 1 NON-injected lesion) was seen in 9/12 patients (75%).  10 patients were evaluable for immune response:  4 with partial regression (40%) and 6 had progressive disease, though later one PD was later found to be a complete response by resection.  The 2 nonevaluable patients had regression of multiple skin lesions.  An increase in the frequency of IFN producing CD8+ T cell was detected in 6/8 abscopal responders.  Tbet+ and granzyme B+ CD8+ T cells were observed in 4/5 and 3/5 responders tested, respectively.  Researchers plan to conduct a phase II trial using IT Ipi/IL-2 in conjunction with systemic immunotherapy.

Final data from CALM: A phase II study of Coxsackievirus A21 (CVA21) oncolytic virus immunotherapy in patients with advanced melanoma.  ASCO - J Clin Oncol 33, 2015.  Andtbacka, Curti, Kaufman, Daniels, et al.

CVA21 is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21.  Intratumal injection initiates preferential tumor cell infection, cell lysis [death] and enhancement of a systemic anti-tumor immune response.  The CALM study looked at 57 patients with treated or untreated, unresectable Stage IIIC-IV melanoma.  Patients were given injections on study days 1, 3, 5, 8, and 22, then every 3 weeks for a further 6 injections.  Patients showing immune-related progression-free survival or better at 6 months were eligible for 9 additional injections.  RESULTS:  21 of 57 (38%) patients displayed progression free survival at 6 months with median PFS of 4.2 months.  Overall response rate was 28% (16 of 57) with a more than 6 month durable response rate of 19% (11 of 57).  Median time to response was 2.8 months, 1 year survival rate was 75% (43 of 57 patients).  At more than 16 months, median duration of response in responders and median overall survival for all patients was not yet reached.  Most common side effects = Grade 1 fatigue, chills, local injection site reaction, and fever.  No grade 3 or 4 reactions.  Further studies with CVA21 in combination with other immunotherapies are in process.

Another recent intralesional therapy report, but NOT from ASCO:

Intralesional administration of L19-IL2/L19-TNF in stage III or stage IV  melanoma patients:  results of a phase II study.  Cancer Immu Imm. 2015 May 14. Danielli, Patuzzo, Di Giaomo, et al.

IT injection of IL2 has shown promise for cutaneous melanoma patients.  We recently reported that the IT injection of L19-IL2, an immunocytokine combining IL2 and the human monoclonal antibody fragment L19, resulted in efficient regional control of disease progression, increased time to distant metastasis and evidence of effect on circulating immune cell populations.  Results of phase II clinical trial with intralesional administration of L19-IL2 and L19-TNF in patients with stage IIIC and IVM1 metastatic melanoma, who were not surgical candidates.  In 20 patients, 32 melanoma lesions exhibited complete responses after IT administration of the two products.  Side effects were mainly injection site reactions.  We observed complete responses in 7/13 (53%) NONINJECTED lesions (4 cutaneous and 3 lymph nodes), indicating a systemic activity of the IT therapy.  This therapy represents a simple and effective method for the local control of inoperable melanoma lesions, with a potential to eradicate them or make them suitable for a facile surgical removal of the residual mass.

Obviously, there are no results from the first study report as yet.  Logically, smaller tumors seem to respond better.  But, I find these intralesional therapies promising. With the possibility of eradication of the injected tumor, potential for abscopal responses, and if only for the reduction of tumor size so that it can then be resected surgically with a very benign side effect profile...it sounds good to me.  The combination of IT injections with systemic immune therapies just makes sense to me.  Of course, time will tell.  But, I think I'd certainly try it if I had the need.  Wishing all my fellow ratties well. - c

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

Radiation alone....not such a good idea in melanoma!!!

Though more and more data indicates that when radiation is COMBINED with other therapies, melanoma patients can reap local, systemic and even abscopal benefits.  However, as noted in this previous post:  Radiation of lymph node basin not so helpful - if that is all that is done
-  radiation alone does not help.

And now there's this:

A retrospective analysis of the role of adjuvant radiotherapy in the treatment of cutaneous melanoma.  Baker, Camacho, Andrews, Mackley.  Cancer Biol Ther. 2016 Aug 15. 

Melanoma is a significant clinical problem, with rising rates of incidence. Surgery is the mainstay of treatment. The role of adjuvant radiotherapy in the control of locoregionally advanced cutaneous melanoma is controversial. A retrospective study of the Surveillance, Epidemiology, and End Results (SEER) database was performed. Patients with locoregionally confined cutaneous melanoma treated surgically between 2004 and 2009 were evaluated, with cancer-specific and all-cause mortality as primary end points. Propensity score matching was used to match 319 radiotherapy patients with 319 non-radiotherapy controls, stratifying by head and neck (HN) and non-head and neck (NHN) primary. Surgery was primarily by wide excision in both the radiotherapy (51.72%) and non-radiotherapy (53.91%) groups. The majority had nodal disease (82.13% vs. 82.44%). White (91.22% vs. 90.59%) males (70.21% vs. 68.96%) predominated. Average ages at diagnosis were 62.27 and 63.02. Using Cox proportional hazards models, radiation conferred decreased survival in all-cause and cancer specific mortality in combined analysis. The NHN group showed significantly decreased 6-year cancer specific survival for radiated patients. The HN group showed a non-significant hazard with radiotherapy. Meaningful differences not captured in the SEER database may exist between cohorts. Based on available SEER data, routine use of adjuvant radiotherapy should be viewed with caution and reserved for high-risk patients. Future trials evaluating patient quality of life may clarify the benefit of adjuvant radiotherapy in high-risk melanoma populations.

Just something to keep in mind!!! - c

ASCO 2016: New studies! Rose Bengal and Pembro for Stage IV y'all!!! Enrolling! For Stage IIIb/c: PV-10 vs T-VEC.

I've been singing about Rose Bengal for some time!  Recently this study showed a bit about how it works...and there are links to previous posts  Now there is this:

Intralesional rose bengal for treatment of melanoma.  ASCO 2016. #9600.  J Clin Oncol 2016.  Agarwala, Andtbacka, Rice, et al.

Background: Intralesional rose bengal (PV-10) is an investigational small molecule ablative immunotherapy that can elicit primary ablation of injected tumors and secondary T-cell activation. Phase 2 testing in Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. PV-10 is currently undergoing phase 3 testing as a single agent in patients with locally advanced cutaneous melanoma and phase 1b testing in combination with immune checkpoint inhibition for more advanced disease. Methods: Study PV-10-MM-31 is an international multicenter, open-label, randomized controlled trial of PV-10 versus investigator’s choice of chemotherapy (dacarbazine or temozolomide) or oncolytic viral therapy (talimogene laherparepvec). A total of 225 subjects with locally advanced cutaneous melanoma (Stage IIIB or Stage IIIC recurrent, satellite or in-transit melanoma) randomized 2:1 will be assessed for progression free survival (PFS) by RECIST 1.1 (using blinded Independent Review Committee assessment of study photography and radiology data). Comprehensive disease assessments, including review of photography and radiology data, are performed at 12 week intervals; clinical assessments of progression status are performed at 28-day intervals. Study PV-10-MM-1201 is an international multicenter, open-label, sequential phase study of PV-10 in combination with pembrolizumab. Stage IV metastatic melanoma patients with at least one injectable cutaneous or subcutaneous lesion who are candidates for pembrolizumab are eligible. In the current phase 1b portion of the study, up to 24 subjects will receive the combination of PV-10 and pembrolizumab (PV-10 + standard of care). In phase 2 an estimated 120 participants will be randomized 1:1 to receive either PV-10 and pembrolizumab or pembrolizumab alone. The primary endpoint for phase 1b is safety and tolerability with PFS a key secondary endpoint; PFS is the primary endpoint for phase 2. Clinical trial information: NCT02288897

Really love that there is a head to head look at PV-10 vs T-VEC.  The fact that they had to throw chemo in there pisses me off...but...  Love the idea of anti-PD1 with intralesionals.  Many researchers have been looking at this as the best way to use intralesional therapy.  

And then there's this:  Rose Bengal and Radiation....Overall response rate of 87%!

A phase 2 study of intralesional PV-10 followed by radiotherapy for localized in transit or recurrent metastatic melanoma.  ASCO 2016. # e21072.  J Clin Oncol 34, 2016.  Foote, Burmeister, Thomas, et al.  

Background: Intralesional rose bengal (IL PV-10) can elicit ablation of injected tumors and a T-cell mediated abscopal effect in untreated lesions. Phase 2 testing in patients with Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. Three patients who progressed received external beam radiotherapy (XRT) to their recurrent lesions with an impressive response without an increased radiation reaction. Methods: An open-label, single-arm phase 2 study was performed to assess efficacy and safety of IL PV-10 followed by XRT. Eligibility included recurrent localized dermal, subcutaneous, in-transit or metastatic malignant melanoma (stage IIIb / IIIc) suitable for intralesional therapy and XRT. Patients received a single course of PV-10 into lesions treatable within a localized radiotherapy field. If CR was not achieved patients received 30 Gy (6 fractions of 5 Gy twice weekly over 3 weeks) 3D conformal radiotherapy (photons or electrons) commencing 6-10 weeks after PV-10. Outcome assessments included ORR and clinical benefit (CR+PR+SD) of in-field target lesions by RECIST criteria, toxicity using CTCAE V3.0, and progression free survival (PFS). Results: There were 15 patients enrolled with 13 completing the radiotherapy component. Two patients had rapidly progressive distant disease following PV-10 injection. The mean age of patients was 69 years. With a median follow up duration of 19.3 months the overall response rate was 87% with 93% clinical benefit on an intent-to-treat basis. The mean time to best response was 3.8 months, mean duration of complete response (PFS) 12.2 months, overall loco regional progression rate 80% and melanoma specific survival 65.5 months.  Size of metastases (less than 10mm) predicted potential for lesion complete response. Treatments were well tolerated with no treatment associated grade 4 or 5 adverse events. Conclusions: The combination of IL PV-10 and radiotherapy resulted in lesion specific, normal tissue sparing, ablation of melanoma tumors with minimal local or systemic adverse effects. The study results justify expanded evaluation in a randomized trial.

Wow!!! Good luck, ratties! - c