New Stuff!! Treatment options and current trials for melanoma patients! The first installment of this year's ASCO review.

As I expected, there was not a great deal of NEW news for melanoma patients coming out of ASCO this year.  However, there were a few new things in the works as well as supporting and dismissive data - (this last often being under reported, but certainly important!!!) - for some existing ideas/treatment strategies.  Over the next few days I will be posting some of the hits and misses (from my perspective) with my take (in red).  Here we go....

#1:  I first reported on NKTR in 2013.  Click here for that report as well as abstracts and analysis from 2018.  After examining the Phase 1 and Phase 2 reports of the PIVOT trial I wrote:

"...back to NKTR-214 combined with nivo.  Like many drugs/trials in cancer/melanoma world, the Phase 1 trials were super promising.  Phase II results were a little less so.  Responses as noted in the article were "(ORR) of 50% in treatment-naïve patients with melanoma, including an ORR of 42% in PD-L1–negative patients".  We have already determined that treatment naive patients tend to have the best responses.  But even so, 50% beats 40%.  Additionally, we also know that PD-L1 status has not been particularly definitive in attaining responses to anti-PD-1 drugs, but it is still good to note a 42% ORR in PD-L1 negative patients and that side effects were really no worse in this combo than when anti-PD-1 is taken alone.  So....

I still hold out hope ~ for vaccines, for IDO-inhibitors, and the current responses to NKTR-214 combined with nivo to hold.  BUT!  Unlike Melanoma Big Dogs in their ivory towers....we canaries in the coalmines...the ratties...you and me...can't afford to pontificate on the hypothetical.  We have to deal with the real live results that are happening for real.  Today.  To us."

That's how I look at melanoma research!!!!   ALWAYS! Now....this:

CA045-001: A phase III, randomized, open label study of bempegaldesleukin (NKTR-214) plus nivolumab (NIVO) versus NIVO monotherapy in patients (pts) with previously untreated, unresectable or metastatic melanoma (MEL).  2019 ASCO.  Nikhil, Khushalani, Diab, .... Sznol, Long.  J Clin Oncol 37, 2019 (suppl; abstr TPS9601)

Background: Standard of care for pts with previously untreated, unresectable or metastatic MEL includes checkpoint inhibitors. Bempegaldesleukin is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor to activate and proliferate effector CD8+ T and NK cells over T-regulatory cells in the tumor (Hurwitz ME et al. ASCO GU 2017). In the dose-expansion phase of the phase 1/2 PIVOT-02 trial, bempegaldesleukin + NIVO was well tolerated at the recommended phase 2 dose (RP2D; bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W), and previously untreated pts with MEL receiving the RP2D achieved an objective response rate (ORR) of 20/38 (53%) and a complete response of 9/38 (24%) by independent radiology review (Diab A et al. SITC 2018). Presented is the design of the first phase 3 trial in the bempegaldesleukin + NIVO development program in pts with previously untreated, unresectable or metastatic MEL. Methods: This phase 3, randomized, open-label study aims to evaluate the effectiveness, safety, and tolerability of bempegaldesleukin + NIVO (NCT03635983). Eligible pts are greater that/= to 2 y with histologically confirmed stage III (unresectable) or stage IV MEL and ECOG PS less that/= to 1 or Lansky PS greater than/= to 80% (minors 12-17 y). Pts are ineligible if they have active brain or leptomeningeal metastases, uveal MEL, or a recurrence within 6 mo of completing adjuvant treatment with any approved agent. Pts will be stratified by PD-L1 status (measured using PD-L1 IHC 28-8 pharmDx), BRAF mutation status, and lactate dehydrogenase level, and will be randomized to receive bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W or NIVO 360 mg IV Q3W up to 24 mo, or until progression or unacceptable toxicity (N ~ 764). Primary endpoints are ORR and progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints include ORR and PFS by investigator, ORR and PFS by BICR in biomarker population, OS in biomarker population, and safety. Additional endpoints include pharmacokinetics and quality-of-life assessment. Clinical trial information: NCT03635983

So, this is an open and recruiting trial.  It is randomized.  Some folks will be getting the NKTR-214 drug with nivo, some will get nivo only.  Prior ORR of 53% is better than the usual of about 40% to anti-PD-1 products given alone, but about equal to the ipi/nivo combo.  If the side effects of this combo is less than those caused by ipi/nivo, that could be a good thing.  Lots of the usual melanoma peeps are excluded.  But, there you go.

#2: In 2017, I posted:  IMO-2125, a TLR agonist combined with Yervoy (ipi) for folks with melanoma refractory to anti-PD-1 - writing:

"Hmmm.....  Well, it is certainly a fact that we have folks who fail to gain effective control of their melanoma with anti-PD-1 and its 40% response rate, leaving them in desperate need of an effective therapy!  It is also true that I encourage and fully support looking at any and all possible treatments to help them.  Yet, I remain a little puzzled here.  This statement sounds strong, but is substantially lacking in, hmmm....what's the word??????  "...data from multiple parameters of immune markers from tumor biopsies have been very informative in establishing proof-of-mechanism and supporting the dose selection for the Phase 2 portion of the trial.”  Oh!  I know what it is....DATA!!!!!!!!!!!!!!!  This report tells us NOTHING about how the folks in the phase 1 trial are doing!!!

An interesting aside:  The name TLR, toll-like receptor, came from the appearance the fruit fly larvae developed when used as subjects by researchers to isolate the molecule's function.  The larvae in whom the receptor was changed, looked very peculiar, or "droll", according to the German researchers who won a Nobel prize in medicine for this work.  And the German word for "droll" (i.e. funny) is "toll"!  The more you know....

While I hope IMO-2125 will absolutely be the cure for ever so many cancers, including melanoma, we need to remember that current intratumoral/intralesional therapies that are being combined with immunotherapy daily, to good effect, are available for melanoma patients in need and come WITH data supporting their efficacy!  Here's a post reviewing a wide variety of them and the DATA required for them to sally forth:

ASCO 2017: All things intralesional/intratumoral

If TLR agonists become the next great thing....will we all be cured of our melanoma AND have a great sense of humor...or just look a little funny?????  Hang tough ratties!  The road is long with lots of tolls!  And I mean LOTS!!! - c"

Now, there's this:

ILLUMINATE 301: A randomized phase 3 study of tilsotolimod in combination with ipilimumab compared with ipilimumab alone in patients with advanced melanoma following progression on or after anti-PD-1 therapy.  2019 ASCO.  Butler, Rober, Negrier....Ascierto, et al.  J Clin Oncol 37, 2019 (suppl; abstr TPS9599)

Background: Tilsotolimod (IMO-2125) is a Toll-like receptor (TLR) 9 agonist with potent immunostimulating activity. In an ongoing Phase 1/2 clinical study in patients with advanced melanoma who progressed on or after anti-PD-1 therapy (NCT02644967), intratumoral (IT) tilsotolimod with ipilimumab was well-tolerated, demonstrating durable responses (including complete response; 21 months), dendritic cell activation, type I interferon response, CD8+ T-cell proliferation in responders, and an abscopal effect. Methods: ILLUMINATE 301 (NCT03445533) is a randomized phase 3 global, multi-center, open-label study of IT tilsotolimod (8 mg) in combination with ipilimumab (3 mg/kg) versus ipilimumab monotherapy in patients with advanced melanoma and progression on or after anti-PD-1 therapy. Eligible patients are greater than/= to 18 years with histologically confirmed unresectable Stage III or Stage IV melanoma, greater than/= to 1 measurable lesion accessible for injection (superficial or visceral, the latter with image guidance), ECOG PS 1, and adequate organ function. Exclusion criteria include prior TLR agonists, prior ipilimumab (except adjuvant ≥12 weeks before progression), and CNS disease other than stable brain metastases. Patients are randomized 1:1 and stratified by duration of prior anti-PD-1.

So....another recruiting option for those who have progressed on anti-PD-1 and have an injectable lesions.  Stage III or IV melanoma ratties will be randomized to get either injections of tilsotolimod  (IMO-2125) directly into their lesion along with ipi or ipi alone.  You cannot have already taken a TLR agonist, ipi (unless it was only as adjuvant more than 12 weeks before progression) and can have no CNS disease other than stable brain mets.

#3:  Here's some background re: TIM-3 from 2016 and Dr. Jeff Weber: 
The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down - This interview/report is pretty cool and clear. I'll just let the Wizard break it down -  Now, this:

A phase Ia/b study of TIM-3/PD-L1 bispecific antibody in patients with advanced solid tumors.  2019 ASCO.  Hellmann, Shimizu, Toshihiko, Hodi, et al.  J Clin Oncol 37, 2019.

Background: Programmed cell death 1 immune checkpoint inhibitors (anti-PD-1, anti-PD-L1) have demonstrated clinical benefit in a subset of patients with manageable safety across a variety of tumor types. T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) can be co-expressed with PD-1 on exhausted T-cells and may be upregulated in tumors refractory to anti-PD-1 therapy (Koyama et al. 2016). Pre-clinical studies demonstrated that blockade of both PD-1 and TIM-3 improved survival of tumor-bearing mice compared to blocking anti-PD-1 only (Koyama et al. 2016). LY3415244 is a TIM-3/PD-L1 bispecific antibody that has the ability to target and inhibit both TIM-3 and PD-L1 and the potential to overcome primary and acquired anti-PD-(L)1 resistance by a novel mechanism to bridge TIM-3- and PD-L1-expressing cells. Methods: Study JZDA is a multicenter, nonrandomized, open-label, Phase 1a/1b study of LY3415244 in patients with advanced solid tumors. In Phase 1a, subjects with any tumor type who are either PD-(L)1 inhibitor-naïve or exposed are eligible. In Phase 1b, expansion cohorts are planned in subjects with PD-(L)1-experienced NSCLC, urothelial carcinoma, and melanoma. Patients with malignant mesothelioma are not required to have received prior anti-PD-(L)1 therapy. The primary objective is to assess safety and tolerability of LY3415244 and identify the recommended Phase 2 dose (RP2D) in Phase 1a (dose escalation). Safety and tolerability of the RP2D will be assessed in Phase 1b (dose expansion). The secondary objectives are to assess the pharmacokinetics of LY3415244 in Phase 1a/1b and assess early antitumor activity of LY3415244 in Phase 1b cohorts. Pre- and on-treatment biopsies will be obtained to explore potential biomarkers of response. During Phase 1a, dose escalation cohorts will proceed via a modified toxicity probability interval-2 (mTPI-2) design with a 1-cycle (28-day) dose-limiting toxicity (DLT) observation period. LY3415244 will be dosed intravenously every 2 weeks. Data from Phase 1a will determine the RP2D, which will be used for all cohorts in Phase 1b. The study is currently open to enrollment. Clinical trial information: NCT03752177.

I seems that you can already have had anti-PD-1, or not, and still qualify.  Folks with NSCLC, urothelial carcinoma or melanoma may enter.  Initially, it is a just a dose limiting study...how much can you give without making folks grow 2 heads?...but then they are also going to look at the impact on the tumors as well.  Early days for this one, but....

#4:  TNF is tumor necrosis factor is a protein that plays a role in cell life, differentiation, growth, and death and has a lot to do with inflammation in our bodies.  In cancer, it's even more complicated.  In this article, the authors note: "In regard to cancer, TNF is a double-dealer. On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates cancer cells’ growth, proliferation, invasion and metastasis, and tumor angiogenesis. On the other hand, TNF could be a cancer killer. The property of TNF in inducing cancer cell death renders it a potential cancer therapeutic, although much work is needed to reduce its toxicity for systematic TNF administration. Recent studies have focused on sensitizing cancer cells to TNF-induced apoptosis through inhibiting survival signals such as NF-κB, by combined therapy."

Now, there's this:

Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy.  Perez-Ruiz, Minute, Otano, et al.  Nature. 2019 May 1. 

Combined PD-1 and CTLA-4-targeted immunotherapy with nivolumab and ipilimumab is effective against melanoma, renal cell carcinoma and non-small-cell lung cancer. However, this comes at the cost of frequent, serious immune-related adverse events, necessitating a reduction in the recommended dose of ipilimumab that is given to patients. In mice, co-treatment with surrogate anti-PD-1 and anti-CTLA-4 monoclonal antibodies is effective in transplantable cancer models, but also exacerbates autoimmune colitis. Here we show that treating mice with clinically available TNF inhibitors concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, improves anti-tumour efficacy. Notably, TNF is upregulated in the intestine of patients suffering from colitis after dual ipilimumab and nivolumab treatment. We created a model in which Rag2^-/-Il2rg^-/- mice were adoptively transferred with human peripheral blood mononuclear cells, causing graft-versus-host disease that was further exacerbated by ipilimumab and nivolumab treatment. When human colon cancer cells were xenografted into these mice, prophylactic blockade of human TNF improved colitis and hepatitis in xenografted mice, and moreover, immunotherapeutic control of xenografted tumours was retained. Our results provide clinically feasible strategies to dissociate efficacy and toxicity in the use of combined immune checkpoint blockade for cancer immunotherapy.

Knowing that TNF is "upregulated in the intestines of patients suffering from colitis" due to ipi/nivo, these researchers gave mice a TNF inhibitor BEFORE treating them with ipi/nivo.  Per this report, blocking TNF improved episodes of colitis and hepatitis caused by ipi/nivo in these poor mice AND the ipi/nivo was still effective against their tumors.  Let's hope it works in real live ratties!!

#5:  TIL is complicated in lots of ways.  I posted this in 2016:  TIL - Tumor infiltrating lymphocytes  writing in part:

"What is TIL?  TIL (Tumor infiltrating lymphocytes) are used in an ACT (adoptive cell transfer) therapy like this:  A tumor is removed from the patient's body.  Lymphocytes are collected from it.  Those lymphocytes are tested in order to identify the cells that show the greatest anti-tumor activity.  Then....those particular cells are grown in a lab for several weeks.  If the TIL cells grow sufficiently, the patient is given a body pounding dosing of chemotherapy to rid the body of other lymphocytes so that the new TIL batch will be accepted more readily when they are infused with no other immune cells there to attack them.  The newly grown lymphocytes are then returned to the patient in an infusion along with a cytokine (immune stimulating agent) like IL2 (interleukin 2).  In numerous studies TIL demonstrates a 50% response rate in patients with metastatic melanoma."

"So....basically.  A tumor is harvested.  T-cells are extracted from it...with the idea that they were good soldiers who had already recognized and were in the process of attacking that tumor.  To increase their numbers...they are grown in a dish.  To further their interests...the patient (ie the battlefield) is injected with bad stuff (IL-2, IL-21, or cyclophosphomide and fludarabine, are frequently used) to kill off T-cells that might try to block their fight with the tumor...and/or support the good T-cells...which are then sent back into battle (ie injected into the patient)!" 

Further, I posted this earlier this year:  Baseline levels of IL-9 predicted response to Adoptive cell therapy (ACT) using TIL in melanoma and a complete response in TIL paired with nivo (a case study)  Where it was noted that:  "Best overall response for the entire cohort was 42%; 47% in 43 checkpoint naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4 naïve patients and 8.6 months in patients with prior CTLA4 blockade. "

Growing useful cells to be injected back to the patient is tricky and just one of many obstacles in TIL therapy.  As the process has advanced, it has diverged into a variety of techniques and methods that can be utilized.  Now, there's this:

Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1.  2019 ASCO.  Sasnaik, Nikhill,Khushalani, et al.  J Clin Oncol 37, 2019 (suppl; abstr 2518)

Background: Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable long-term responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel (LN-144), a centrally manufactured autologous TIL therapy are presented. Methods: C-144-01 is a global Phase 2 open-label, multicenter study of the efficacy and safety of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 55) patients who received cryopreserved lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. Results: In 55 patients with Stage IIIC/IV unresectable melanoma, 3.1 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 24%), high baseline tumor burden (110 mm mean target lesion sum of diameters), ORR was 38% (2 CR, 18 PR, 1 uPR). Of 21 responders, 4 have progressed to date with median follow up of 7.4 months. Overall disease control was 76%. Improved responses in some patients were observed with longer follow up. Most (54) patients progressed on prior anti-PD1 and those with PD-L1 negative status were among responders. Mean cells infused was 28 x109. Median IL-2 doses administered was 6.0. Adverse events resolved to baseline, 2 weeks post TIL infusion, a potentially important benefit of one-time TIL therapy. Conclusions: Lifileucel treatment results in 38% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who received prior anti-PD1 and BRAF/MEK inhibitor if BRAF mutated. Based on these data, a new Cohort 4 in C-144-01 has been initiated to support lifileucel registration. Clinical trial information: NCT0236057

Here 55 Stage III/IV melanoma patients previously treated with anti-PD-1, ipi, and/or BRAF/MEK, with progressive disease and high tumor burden were given "cryopreserved lifileucel" derived from "tumors resected" at several institutions, then "processed" at a central facility for "TIL production in a 22-day process" then "cryopreserved and shipped to sites".  As is typical with TIL therapy, patients were given one of the nasty pre-treatment concoctions to kill off their existing lymphocytes, were then given a single infusion of lifileucel, followed by up to 6 doses of hell (I mean IL-2).  ORR = 38%.  Of 21 initial responders, 4 have progressed over the f/u of 7.4 months.  Overall disease control was 76%.  Both folks who had progressed on anti-PD-1 and those with PD-L1 negative status were among the responders.  Based on this result, a new cohort is recruiting.

#6:  The "microbiome" craze is not exactly 'new' as it has taken over the universe! BUT!!!  How much is hype?  How much is real?  How can we drill down on the details?  How can we harness what we know to impact treatments such that patients benefit?  The next 3 posts address this topic.  Now, there's this:

A phase I/II study of live biotherapeutic MRx0518 in combination with pembrolizumab in patients who have progressed on prior anti-PD-1 therapy.  2019 ASCO.  Shubham, Imke, Amishi, et al. J Clin Oncol 37, 2019 (suppl; abstr TPS2670) 

Background: The gut microbiome has emerged as a new therapeutic target to augment the efficacy of immune checkpoint blockade. MRx0518 is a novel, gut microbiome-derived, oral live biotherapeutic, designed to induce a broad immunostimulatory response to re-engage PD-1 inhibitor activity. Preclinical studies showed that MRx0518 reduced tumour growth in models of kidney, lung and breast cancer. MRx0518 increased CD4 and CD8 T cell and NK cell infiltration into the tumour and decreased Tregs. Upregulation of tumour TLR5 was observed and linked to the bacterial flagellin moiety, which was shown to strongly induce NFκB, cytokine responses and IFNγ+ CD4 and CD8 T cells. The study, one of the first oncology trials conducted with live biotherapeutics, is a single center, open label, safety and preliminary efficacy study of MRx0518 in combination with pembrolizumab in patients with solid tumors who have progressed on PD-1 inhibitors. Methods: Trial consists of 2 parts. In Part A, 12 patients receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 with a DLT period of 1 cycle (21 days). In Part B, up to 30 patients per cohort (NSCLC, Urothelial, Renal and Melanoma) will receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 for up to 35 cycles or until disease progression per RECIST 1.1. The primary end points are safety and tolerability of MRx0518 in combination with pembrolizumab (Parts A and B) and clinical benefit of MRx0518 in combination with pembrolizumab (Part B). Secondary end points are objective response rate, duration of response, disease control rate, and progression-free survival. Exploratory end points include biomarkers of treatment effect, effect on microbiota and overall survival. Recruitment is ongoing. Clinical trial information: NCT03637803

Here, researchers are going to give the first 12 patients with solid tumors who have progressed on anti-PD-1, Pembro every 3 weeks along with a capsule of MRx0518, a "live biotherapeutic", taken by mouth, twice a day for one 21 day cycle.  In part b, the plan is that 30 patients could be given the same for up to 35 cycles or until disease progression.  My only concern here would be the fact that we've found that folks who took probiotics from a bottle did not do so well, while those that got their cooties from foods like Kefir, kimchi, yogurt, sauerkraut, etc. - did better.  If I were to consider participation in this study, I'd be asking my doc about that.

#7:  As I noted above, these last two reports are more along the lines of ~ "What once was old is new again!" I've been talking about the Cooties in our Gut since 2015, putting it all together in this post from 2018:  Microbes again...and how they may be associated with improved response to anti-PD-1 for melanoma patients...and you might even laugh!!!  Still, there is much we don't understand about how all this works.  Now, there's this:

Gut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5^-/- mice.  Li, Tinoco, Elmen, et al.  Nat Commun. 2019 Apr 2.

Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells. Reduced UPR expression is also seen in murine and human melanoma tumor specimens that responded to immune checkpoint therapy. Co-housing of Rnf5^-/- and WT mice abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium, enriched in Rnf5^-/- mice, establishes anti-tumor immunity and restricts melanoma growth in germ-free WT mice. Altered UPR signaling, exemplified in Rnf5^-/- mice, coincides with altered gut microbiota composition and anti-tumor immunity to control melanoma growth.

So, a lot of fancy words to say that mice with a certain microbiome component (less UPR expression) responded better to immunotherapy.  Further, when those mice lived with mice whose gut initially did not possess those properties, researchers found that they too developed an altered gut flora and a greater ability to restrict the growth of melanoma.  Bottom line:  Live with somebody who has the right cooties!  (If you can figure out who exactly that is!!!)

#8:  Given the fact that a certain "microbiome" aids our responses to immunotherapy while a different one does not, it makes sense that antibiotics, which kill off bacteria that are trying to do us harm as well as those who may do a body good, could be problematic when trying to foster cooties that improve our response to immunotherapy.  Here are some earlier articles and explanations:

This from 2017:  Antibiotic use MAY decrease effectiveness of immunotherapy?????

And this from April of this year:  DECREASED progression free survival in melanoma patients treated with antibiotics prior to or at start of immunotherapy!!!!  In that study it was noted that, despite - "Small numbers. ..the 10 folks, from the 74 advanced melanoma peeps examined, who were given antibiotics within 30 days of their immunotherapy, had more resistance to treatment, a shorter length of progression free survival (2.4 vs 7.3 months) and overall survival was shorter at 10.7 months vs 18.3 months." 

Now, there's this:

Effect of antibiotic exposure in patients with metastatic melanoma treated with PD-1 inhibitor or CTLA-4 inhibitor or a combination of both.  2019 ASCO. Kapoor, Runnels, Boyce, et al.  J Clin Oncol 37, 2019 (suppl; abstr e14141)

Background: Pre clinical studies have demonstrated the effect of gut microbiome in the efficacy of immune check point inhibitors. The effect of antibiotic exposure to patients receiving PD-1/CTLA-4 inhibitor therapy has not been extensively studied, especially in metastatic melanoma. In this study, we demonstrate the effect of antibiotic exposure to metastatic melanoma patients receiving PD-1/CTLA-4 inhibitor therapy. Methods: We performed a retrospective analysis of 108 patients with stage 4 metastatic melanoma who received immunotherapy with PD-1 inhibitors or CTLA-4 inhibitors or combination of both between Nov 2010 and Oct 2017. Patients were divided into Abx(+) and Abx(-) groups that were defined as patients exposed or not exposed to antibiotics respectively. The time frame for antibiotic exposure was taken from 6 months prior to 1 month after initiation of immunotherapy. We compared progression free survival (PFS), overall survival (OS) and response rate (RR) between the two groups. RR was calculated based on the entire length of follow-up.  Results: Out of 108 patients, 66 were men, with a mean age 64.6 ± 15.1 years. 46 patients were exposed to antibiotics of varied classes. Median PFS in abx(+) group [88 days] was shorter as compared to abx(-) group [322 days]. Patients in abx(-) group had a 68% reduced risk of progression within 200 days of immunotherapy initiation adjusting for sex, age and number of immunotherapy cycles . Median OS in ab(+) group [294 days] was shorter as compared to abx(-) group [573 days]. Response rate defined as percentage of patients whose cancer was stable or entered remission was 12.9% in abx(-) group as compared to 8.7% ab(+) group. Patients in abx(-) group had a 52% reduced risk of death adjusting for sex, age and number of immunotherapy cycles. Conclusions: Antibiotic exposure is associated with poorer outcomes in patients with advanced metastatic melanoma being treated with PD-1/CTLA-4 inhibitors which is likely related to alteration of gut microbiome. Antibiotics should be prescribed with caution in patients undergoing treatment with immune check point inhibitors. These data should be validated in a larger patient population.

In this retrospective study of 108 melanoma patients treated with immunotherapy, it was noted that 46 were given antibiotics at some point between 6 months prior and 1 month after starting their immunotherapy treatment.  PFS was 88 days in those who took antibiotics and 322 days in the group who didn't.  OS was 294 days in the antibiotic group - 573 days in the non-antibiotic group.  Response rate was 8.7% in the group that had taken antibiotics vs 12.9% in the group that had not been exposed to antibiotics.  As I wrote in the post I put up in April:  "So...if you really NEED antibiotics, they may save your life and will certainly decrease misery. BUT, if you DON'T really NEED them...they can cause harm, in lots of ways."

WHEW!!!  Melanoma is a lot.  A lot of crap.  And an actual crap shoot for far too many!  But, just like today...

...there is still beauty, despite the storm.

More to come. c

IMO-2125, a TLR agonist combined with Yervoy (ipi) for folks with melanoma refractory to anti-PD-1

So, one of the MRF peeps put up a bit of an ad for this treatment...not entirely sure why, as that is not usually their role.  Perhaps they were just letting folks looking for a treatment option after failing anti-PD-1 know this trial was enrolling.  But, with so little intel out about this study and so many other options available - it piqued my interest.  It was quickly apparent that it is hard to find much info on it other than the super slick "presentations" made by the company who makes it, Idera, and the company who wants you to join their trial, MD Anderson, like these:

A Phase 1/2 trial of intratumoral (i.t.) IMO-2125 (IMO) in combination with checkpoint inhibitors (CPI) in PD-(L)1-refractory melanoma - out of MD Anderson

Idera Press Release for investors

But, when my intrepid medical researcher, partner in crime and all things got on the case, he found this:  Melanoma News Today - report from April 2017

It reads as follows:

Combining IMO-2125 and Yervoy Shows Promise in Certain Metastatic Melanoma Patients   By:  Daniela Semedo, Melanoma News Today, April 2017.

Combining {Idera's] intratumoral IMO-2125 treatment with Yervoy (ipilimumab) may be a promising treatment approach for patients with metastatic melanoma who are refractory to anti-PD-1 therapies, according to preliminary data from a Phase 1/2 clinical trial.

“We are very pleased with the progress to date in the Phase 1 dose escalation trial of IMO-2125 in combination with ipilimumab, and with the outcomes observed,” Joanna Horobin, Idera’s chief medical officer, said in a press release. (Possibly the one I noted above.)

“IMO-2125 in combination with ipilimumab demonstrated preliminary evidence of meaningful clinical activity in this anti-PD-1 refractory metastatic melanoma patient population which represents a high unmet medical need,” she said.

“All dose levels have been well tolerated and did not exacerbate the safety issues commonly observed with ipilimumab,” Horobin said. “Furthermore, data from multiple parameters of immune markers from tumor biopsies have been very informative in establishing proof-of-mechanism and supporting the dose selection for the Phase 2 portion of the trial.”

IMO-2125, a toll-like receptor (TLR) agonist, is designed to activate cells from the innate immune system and induce the production of interferon — a potent activator of the immune system. Together, this is thought to lead to the infiltration of tumor-killing T-cells.

Because tumors have developed a method to impair T-cells from recognizing and attacking them, Idera believes that the drug could work in synergy with known and approved immune checkpoint inhibitors.

The open-label Phase 1/2 study (NCT02644967) was designed to assess the safety and preliminary effectiveness of intratumoral IMO-2125 in combination with the CTLA-4 inhibitor Yervoy or the PD-1 inhibitor Keytruda (pembrolizumab) in patients with metastatic melanoma who progressed after receiving anti-PD-1 therapies.  The study was set to be conducted in two parts: a dose-escalation portion (Phase 1) to evaluate safety and tolerability of multiple dose levels, and a Phase 2 expansion portion to assess efficacy.

While the Phase 1 dose escalation of IMO-2125 in combination with Keytruda is ongoing, the company has now announced that the Phase 1 part assessing IMO-2125 plus Yervoy has met the pre-specified futility assessment, meaning that the combination reached the established efficacy cut-off.

The company announced that all dose levels of IMO-2125 were well tolerated, and that the 8 mg dose level was established as the recommended Phase 2 dose.

Nine participants out of an expected 21 have enrolled in the Phase 2 portion of the trial assessing the objective response rate of IMO-2125 in combination with Yervoy. Data will be compared with historical controls treated with Yervoy alone.

Houston’s MD Anderson Cancer Center will continue to lead the study and will be joined by other clinical sites. Idera expects to have overall response rate (ORR) data early next year.

“I am very encouraged by the tremendous progress that has been made to date to advance us to this important stage in IMO-2125’s development cycle,” said Vincent Milano, Idera’s CEO. “There is a very clear unmet medical need for those patients for whom current checkpoint inhibitor therapies are not providing adequate solutions.

“We are incredibly focused on advancing this program as rapidly as possible for these patients, and we are also looking forward to exploring areas outside of melanoma in which intratumoral IMO-2125 may also serve an important role through its unique mechanism of action within the tumor microenvironment,” he said.

Idera also said it has started meeting with regulatory agencies about the best path to follow to register the combined treatment of IMO-2125 and Yervoy in patients with PD-1 refractory metastatic melanoma.

In addition, the company said the Phase 1 clinical trial evaluating the combined treatment of intratumoral IMO-2125 and Keytruda in PD-1 patients with refractory melanoma is enrolling as planned.  Moreover, a Phase 1 clinical trial evaluating intratumoral IMO-2125 alone (NCT03052205) in multiple tumor types should be enrolling the first patient in coming months.

Hmmm.....  Well, it is certainly a fact that we have folks who fail to gain effective control of their melanoma with anti-PD-1 and it's 40% response rate, leaving them in desperate need of an effective therapy!  It is also true that I encourage and fully support looking at any and all possible treatments to help them.  Yet, I remain a little puzzled here.  This statement sounds strong, but is substantially lacking in, hmmm....what's the word??????  "...data from multiple parameters of immune markers from tumor biopsies have been very informative in establishing proof-of-mechanism and supporting the dose selection for the Phase 2 portion of the trial.”  Oh!  I know what it is....DATA!!!!!!!!!!!!!!!  This report tells us NOTHING about how the folks in the phase 1 trial are doing!!!

An interesting aside:  The name TLR, toll-like receptor, came from the appearance the fruit fly larvae developed when used as subjects by researchers to isolate the molecule's function.  The larvae in whom the receptor was changed, looked very peculiar, or "droll", according to the German researchers who won a Nobel prize in medicine for this work.  And the German word for "droll" (i.e. funny) is "toll"!  The more you know....

While I hope IMO-2125 will absolutely be the cure for ever so many cancers, including melanoma, we need to remember that current intratumoral/intralesional therapies that are being combined with immunotherapy daily, to good effect, are available for melanoma patients in need and come WITH data supporting their efficacy!  Here's a post reviewing a wide variety of them and the DATA required for them to sally forth:

ASCO 2017: All things intralesional/intratumoral

If TLR agonists become the next great thing....will we all be cured of our melanoma AND have a great sense of humor...or just look a little funny?????  Hang tough ratties!  The road is long with lots of tolls!  And I mean LOTS!!! - c

ISF35 - the viral vector for a CD40 agonist - used as an intratumoral/intralesional melanoma treatment!!!

On the subject of intratumoral treatment of melanoma - drugs that are injected directly into the tumor, as the prior post on IMO-2125, a TLR agonist discussed, along with ALL these other intralesional/intratumoral therapies covered here:  ASCO 2017: All things intralesional/intratumoral
 - we've learned a couple of things:

1.  These drugs can have significant "by-stander" effect.  Meaning - they can kill not only the tumor they are injected it...but others...distant from the site of the injected tumor.

2.  As many melanoma experts said years ago, they will most likely turn out to be most effective when paired with systemic immunotherapy (as most of the research that is on-going is doing currently.

But...there's another one on the horizon.  It's been a long time in coming.  I posted this back in 2014:

CD40 Antibody therapy for melanoma....another way to activate the immune system?

And now, there's this:

Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain. Singh, Vianden, Cantwell, et al. Nat Commun. 2017 Nov 13.

CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8⁺ T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8⁺ T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy. Triple combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and noninjected subcutaneous tumors, as well as melanoma tumors in the brain. Therapeutic efficacy is associated with increases in the systemic level of tumor-specific CD8⁺ T cells, and an increased ratio of intratumoral CD8⁺ T cells to CD4⁺ Tregs. These results provide a proof of concept of systemic antitumor activity after intratumoral CD40 triggering with ISF35 in combination with checkpoint blockade for multifocal cancer, including the brain.

A triple-decker approach!!!  I like it!!  Now where is the slick MD Anderson poster boards for this one?????

Fingers crossed, ratties!  Fingers crossed. - c

Imiquimod and Mebendazole...drugs repurposed for mousie melanoma

Folks in melanoma world tend to go nuts when reports like these hit the news stand.  Partly out of desperation for an effective treatment, but also because sometimes such reports fail to make it clear that these great strides were attained in mousies rather than ratties.  Despite the skepticism my first sentence may convey, mice ARE the first step toward ratties and if they can find a treatment that works for more of my melanoma peeps, I'll take it!!!

First up is imiquimod, a cream that is usually used topically to treat venereal warts, basal cell carcinoma, and actinic keratosis.  These little mice seem to have had it applied topically (??? I think) as well as having it injected in their tail veins (not sure which vein that would be in ratties!!!) followed by radiation and it seemed to make melanoma lesions more responsive to that treatment.

Next there's mebendazole, an old, cheap, oral drug most often used to treat pin worms in kids...but also infestations of many other wormy critters as well as giardia.  Generally, it is safe to use, though in large doses can cause bone marrow suppression.  As an aside, I had a good many doses of this as a child because my mother seemed to have been of the persuasion that an ounce of prevention was worth a pound of cure....not that this med works like that for worms nor melanoma, as I sit here today as a Stage IV melanoma rattie!!!

At any rate, here you go.....

The TLR7 agonist imiquimod induces anti-cancer effects via autophagic cell death and enhances anti-tumoral and systemic immunity during radiotherapy for melanoma. Cho, Lee, Ko, et al. Oncotarget. 2017 Feb 15.

Toll-like receptor (TLR) ligands are strongly considered immune-adjuvants for cancer immunotherapy and have been shown to exert direct anti-cancer effects. This study was performed to evaluate the synergistic anti-cancer and anti-metastatic effects of the TLR7 agonist imiquimod (IMQ) during radiotherapy for melanoma. The pretreatment of B16F10 or B16F1 cells with IMQ combined with γ-ionizing radiation (IR) led to enhanced cell death via autophagy, as demonstrated by increased expression levels of autophagy-related genes, and an increased number of autophagosomes in both cell lines. The results also confirmed that the autophagy process was accelerated via the reactive oxygen species (ROS)-mediated MAPK and NF-κB signaling pathway in the cells pretreated with IMQ combined with IR. Mice subcutaneously injected with melanoma cells showed a reduced tumor growth rate after treatment with IMQ and IR. Treatment with 3-methyladenine (3-MA), ameliorated the anti-cancer effect of IMQ combined with IR. Additionally, the combination therapy enhanced anti-cancer immunity, as demonstrated by an increased number of CD8+ T cells and decreased numbers of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs) in the tumor lesions. Moreover, the combination therapy decreased the number of metastatic nodules in the lungs of mice that were injected with B16F10 cells via the tail vein. In addition, the combination therapy enhanced systemic anti-cancer immunity by increasing the abundances of T cell populations expressing IFN-γ and TNF-α. Therefore, these findings suggest that IMQ could serve as a radiosensitizer and immune booster during radiotherapy for melanoma patients.

The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma.  Simulam-Rosenthal, Dakshanamurthy, Gaur, et al. Oncotarget. 2017 Feb 2.

Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes. Downstream ERK targets for cell cycle, including cMYC, were down-regulated, consistent with S- phase suppression by MBZ+trametinib, while apoptosis markers, including cleaved caspase-3, cleaved PARP and a sub-G1 population, were all increased with time. These data suggest that MBZ, a well-tolerated off-patent approved drug, should be considered as a therapeutic option in combination with trametinib, for patients with NRASQ61mut or other non-V600E BRAF mutant melanomas.  

Thanks to all the dear mousies!! love, rattie

T-VEC in melanoma, after progression on immunotherapy and BRAFi with good results! 3 case reports...

I have been a fan of intralesional (also called intratumoral) therapies for some time...esp in combination with systemic therapy, noting in a prior report ~ "These drugs are injected directly into a relatively superficial melanoma tumor.  They have been found to be effective in not only eradicating the tumor into which they have been injected, but 'by-stander' lesions as well. Researchers feel that they have the most promise when they are combined with a systemic treatment like immunotherapy."

These drugs include:  T-VEC, PV-10, CAVATAK, HF10, SD101 and IMO-2125 (both TLR agonists), ISF35 (a CD40 agonist), and even IL2 has been used in this fashion.  Here's a link to bunches of reports on all of these:  ALL the intralesionals!!!

Here are multiple reports on T-VEC in particular:  All things T-VEC (talimogene laherparepvec)

Now...here are three case reports on melanoma peeps who had failed multiple therapies but gained a response with T-VEC...

Potential clinical and immunotherapeutic utility of talimogene laherparepvec for patients with melanoma after disease progression on immune checkpoint inhibitors and BRAF inhibitors. Chesney, Imbert-Fernandea, Telang, et al. Melanoma Res. March 20, 2018.

Talimogene laherparepvec is a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy for the local treatment of unresectable subcutaneous and nodal tumors in patients with melanoma recurrent after initial surgery. We report on two patients with melanoma who, after progression on numerous systemic therapies, derived clinical benefit from talimogene laherparepvec in an expanded-access protocol. Intralesional talimogene laherparepvec (day 1, greater than/= to 4 ml 10 PFU/ml; after 3 weeks, greater than/= to 4 ml 10 PFU/ml every 2 weeks) was administered until complete response, no injectable tumors, progressive disease, or intolerance occurred. Patient 1 was 71 years old, had stage IIIB disease, and had previously received granulocyte-macrophage colony-stimulating factor, vemurafenib, metformin, ipilimumab, dabrafenib, trametinib, and pembrolizumab. Patient 2 was 45 years old, had stage IIIC disease, and had previously received nivolumab/ipilimumab combination therapy. There were marked reductions in the number and size of melanoma lesions during treatment with talimogene laherparepvec. Both patients experienced mild-to-moderate nausea and vomiting, which were managed using ondansetron, metoclopramide, and pantoprazole. Both patients completed treatment with talimogene laherparepvec in the expanded-access protocol on 24 November 2015, but received talimogene laherparepvec in clinical practice. Patient 1 continues to receive therapy (greater than 60 weeks); patient 2 experienced a complete response at 23 weeks. Immunohistochemistry of a biopsied dermal metastasis from patient 1 showed a marked infiltration of CD4 and CD8 T cells after 1 year of treatment. Talimogene laherparepvec was active in patients with advanced melanoma with disease progression following multiple previous systemic therapies; no new safety signals were identified.

...and the final peep....

Complete intracranial response to talimogene laherparepvec (T-Vec), pembrolizumab and whole brain radiotherapy in a patient with melanoma brain metastases refractory to dual checkpoint-inhibition. Blake, Marks, Gartrell, et al. J Immunother Cancer. 2018 Apr 6.

Immunotherapy, in particular checkpoint blockade, has changed the clinical landscape of metastatic melanoma. Nonetheless, the majority of patients will either be primary refractory or progress over follow up. Management of patients progressing on first-line immunotherapy remains challenging. Expanded treatment options with combination immunotherapy has demonstrated efficacy in patients previously unresponsive to single agent or alternative combination therapy.

We describe the case of a patient with diffusely metastatic melanoma, including brain metastases, who, despite being treated with stereotactic radiosurgery and dual CTLA-4/PD-1 blockade (ipilimumab/nivolumab), developed systemic disease progression and innumerable brain metastases. This patient achieved a complete CNS response and partial systemic response with standard whole brain radiation therapy (WBRT) combined with Talimogene laherparepvec (T-Vec) and pembrolizumab.

Patients who do not respond to one immunotherapy combination may respond during treatment with an alternate combination, even in the presence of multiple brain metastases. Biomarkers are needed to assist clinicians in evidence based clinical decision making after progression on first line immunotherapy to determine whether response can be achieved with second line immunotherapy.

Now...these abstracts describe only 3 peeps.  Patient #1 is still with us a year later and, given the T cell response noted, seems to be benefiting.  Patient #2 attained a complete response.  Patient #3 attained a complete response in the brain and partial in the body.  (I still really hate it when melanoma patients - or anybody really - has to resort to WBR, but desperate times call for desperate measures.) 

So...for what it's worth.  Sounds like something I would certainly be interested in should I have the need.  Hang tough ratties!!! - c

ASCO 2017: All things intralesional/intratumoral

I have long been a fan of intralesional (intratumoral...pick your nomenclature) therapy's potential. These are medications that are injected directly into superficial lesions...which researchers have found can make the injected tumors, as well as distant ones, GO AWAY!!! Additionally, it has long been supposed that if they were combined with systemic immunotherapy they would work even better.

In 2014 I wrote:  "Intralesional melanoma therapy (A procedure in which the "treatment" is directly injected into superficial tumors and in theory, not only does that tumor die, but "by stander" tumors at more distant sites die too!!!) was first recorded back in 1975.  A 75 year old male with 64 melanoma mets just below the skin, as well as junk in his lungs, had 17 superficial lesions injected with Bacille Calmette-Guerin over a period of 8 months. (BCG is a vaccine against some strains of tuberculosis, but does contain a weakened version of the bacteria itself within it.) In the end, all 17 tumors injected resolved and his pulmonary mets diminished by more than 50%!  However, enthusiasm for BCG as a melanoma treatment waned as patients in subsequent trials experienced anaphylactic reactions and death due to disseminated BCG, and randomized trials failed to replicate significant clinical benefit.

Later, intralesional therapy was tried using all sorts of things.  More recently Allovectin-7, OncoVEX, and PV-10 have demonstrated positive results, killing melanoma at the injected site and systemically.  

Today, three years later.... we now know that, unfortunately, Allovectin-7 (velimogen aliplasmid) did not work out and trials were ended by its manufacturer, Vical. However, we do have an additional intralesional: CAVATAK, derived from the Coxsackievirus (a frequent cause of the common cold) produced by Virolytics.   OncoVEX now also called Talimogene Laherparepvec (or T-vec, brand name Imlygic) engineered using the herpes virus and GM-CSF, developed originally by BioVex and now produced by Amgen who bought them out, is still in process. There is also PV-10 generated from Rose Bengal made by Provectus.  It has shown promise in studies I have previously posted and there is this blurb from Fortune magazine in 2016:

"Final results from an ongoing 225-patient melanoma trial of the experimental drug compared to chemotherapy are expected in early 2018. The hope is that the drug, known as PV-10, will prevent melanoma from progressing beyond Stage III, in which the disease has spread but not yet to other organs, and allow patients with more advanced cancer to live longer." 

From a 2016 study that paired PV-10 with radiation there was this:   "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. "

For whatever reason, perhaps due to the immaturity of the data, (In addition to the study referenced above, a study was started in 2016 combining PV-10 with pembro.) PV-10 did not make it to an ASCO presentation this year...not at least any I found. Here is a link to prior posts:  All things PV-10

*************************CAVATAK********************************

CAVATAK has been talked up for a while now.  Here are links to many posts:  All things CAVATAK  In a 2016 report where CAVATAK was used alone, this was reported:  "Responders on the CALM study (16/57 pts, 28.1%) displayed reductions in both injected and non-injected lesions, suggesting the generation of significant host anti-tumor responses. A comparable ORR was observed in pts administered prior immunotherapy, 29.0% (9/31) vs other tx 27.0% (7/26). Interestingly, 26.7% (4/15) and 40% (2/5) of pts previously treated with ipilimumab and talimogene laherparepvec, respectively, developed confirmed responses."

Here, CAVATAK is combined with ipi:

Activity of a novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients previously treated with anti-PD1 blockade therapy.

ASCO 2017. J Clin Oncol 35, 2017. Curti, Richards, Hallmeyer, Faries, Andbacka, et al.

Background: CAVATAK is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21) that when injected into melanoma lesions can increase immune-cell infiltration, up-regulation of γ-INF response and immune-checkpoint genes, including CD122, which may be a potential marker for enhanced anti-tumor activity by anti-CTLA-4 blockade. Intratumoral replication of CVA21 may act as a strong “immune-sequestration signal” to circulating activated T-cells following CTLA-4 blockade. A large unmet need exists for active therapies in melanoma patients (pts) following treatment (tx) with anti-PD1 therapies. We present in a Phase 1 study, the clinical activity of a CVA21/ ipilimumab (ipi) combination following anti–PD1 therapy in advanced melanoma pts. Methods: The Phase Ib MITCI study (NCT02307149) investigated the efficacy and safety of i.t. CVA21 and i.v. ipi in 26 pts with unresectable Stage IIIB/C-IVM1c melanoma with 13 pts previously treated with anti-PD1 therapies. Pts received up to 3 x 10⁸ TCID₅₀CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipi (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. Results: Analysis of the prior anti–PD1 treated pts (n=13) revealed that the combination tx was generally well-tolerated with one case of Gr 3 ipi-related liver toxicity observed. Of the tx population, 54% (7/13) had received prior ipi tx in addition to anti-PD1, 85% (11/13) of pts were stage IV M1b/c, with the median time between the last anti-PD1 and first CVA21 and ipi doses being 5.7 and 8.7 weeks, respectively. The mean number of prior systemic therapies including anti-PD1 tx was 2.6. For all pts completing at least the first investigator response assessment (irWHO criteria at Day 106) we observed a confirmed BORR of 38.0% (3/8) and a DCR (CR+PR+SD) of 88% (7/8). Conclusions: Intratumoral CVA21 + ipilimumab treatment in anti–PD1 treated pts has displayed promising clinical activity together with low adverse toxicity and as such this regimen may represent a valuable tx option for pts that have been administered previous lines of immune checkpoint therapy. 

Here 26 patients (Stage III and IV) - 13 with prior anti-PD-1, had lesions injected with CAVATAK and ipi (3mg/kg) was given 4 times IV.  Best ORR = 38% with a total response rate of 88% when complete response, partial response and stable disease were combined.

**********************************T-VEC*********************

ASCO 2016 began to report the results of T-VEC combined with Pembro, reporting:  "Of the 21 pts enrolled from Dec 2014 – Mar 2015, 48% had IIIB-IVM1a, 52% IVM1b/c, 76% HSV-1+, and 19% BRAFmut+. Median follow-up at data cut was 33 w. All pts received at least one dose of T-VEC+pembro. Tx-related AEs occurred in all pts: 33% G3/4, and no G5. Most common AEs were fatigue (62%), pyrexia (52%), and chills (48%). Per irRC, in 21 pts, confirmed/not yet confirmed objective response rate (ORR) was 48%/57%; CR rate was 14%/24%. Median time to response was 17 wks."

Here is a report from a study using T-VEC alone:  "In a phase 2 trial reported in 2012, 20% of patients achieved a complete response and 28% gained an overall response.  92% of the responses were durable to at least 6 months, and the majority were ongoing with a range of 18-40 months.  Responses were found in patients with all stages and systemic tumors were eradicated in some patients."
Here is a link to posts that are:  All things T-VEC

Here T-VEC plus ipi was compared to ipi alone:

Primary results from a randomized (1:1), open-label phase II study of talimogene laherparepvec (T) and ipilimumab (I) vs I alone in unresected stage IIIB- IV melanoma.

ASCO 2017. J Clin Oncol 35, 2017. Chesney, Puzanov, Ross, et al.

Background: T is a HSV-1-based oncolytic virus designed to selectively replicate in tumors and produce GM-CSF to stimulate antitumor immune responses. I is an anti-CTLA-4 Ab [ipi/Yervoy] that blocks inhibition of activated T cells. This is the first randomized study to evaluate the addition of an oncolytic virus to a checkpoint inhibitor. Methods: The primary endpoint was ORR by immune-related response criteria. Key secondary endpoints: duration of response, disease control rate (DCR), PFS, OS, and safety. Prior treatment was allowed but not required. Pts had unresected stage IIIB-IV melanoma with measurable/injectable tumor(s) and no evidence of immunosuppression. T was given at approved dosing until no injectable tumors, disease progression (PD), or intolerance. I was started at w6 in T+I and at w1 in I at 3 mg/kg IV q3w x 4. Primary analysis occurred 6 m after last pt enrolled. Results: 198 pts were randomized: 98 T+I; 100 I. Characteristics were similar: 54% stage IIIB-IVM1a, 46% IVM1b/c. Median follow up time was 68 w (T+I) and 58 w (I). ORR was 38.8% (T+I) and 18.0% I, Odds ratio (OR) 2.9. 89% T+I and 83% I pts remain in response. Unconfirmed visceral lesion response was 35.5% T+I vs 13.6% I. OS is immature. Of 190 pts (safety set: 95 T+I, 95 I), most common adverse events (AEs) for T+I, I (%) were fatigue (59, 42), chills (53, 3), and diarrhea (42, 35). 28% T+I and 18% I pts had gr greater than/ = to 3 tx-related AE. There were 3 deaths (all unrelated) in T+I: 1 myocardial infarction and 2 PD. Conclusions: ORR was significantly higher for T+I vs I; responses were not limited to injected lesions. Toxicity of T+I combination was tolerable with no unexpected AEs. 

Here patients were Stage III/IV, some had had prior treatment, some not.  98 were given T-VEC and ipi, 100 got only ipi.  ORR to combo = 38.8%.  Ipi alone ORR = 18%.  

******************************************HF-10*******************************

Here is a study using HF-10, another HSV based intralesional, produced by Japanese company TaKaRa combined with ipi:

Final results of a phase II multicenter trial of HF10, a replication-competent HSV-1 oncolytic virus, and ipilimumab combination treatment in patients with stage IIIB-IV unresectable or metastatic melanoma.

ASCO 2017. J Clin Onco 35, 2017. Andtbacka, Ross, Agarwala, ...Grossmann.

Background: HF10 is a bioselected replication-competent oncolytic virus derived from HSV-1. Herein, we report the safety and efficacy data of HF10 + ipilimumab (ipi) combination treatment in a Phase II trial in melanoma. Methods: Key entry criteria: age greater than/= to 18 yrs, ECOG less than/= to 2, Stage IIIB, IIIC, or IV unresectable melanoma, ipi naïve (IV administration) and measurable non-visceral lesion(s) suitable for injection. HF10 injected into single or multiple tumors (1 x 10⁷ TCID₅₀/mL/dose, up to 5mL depending on tumor size and number); 4 injections q1wk; then up to 15 injections q3wk. Four ipi IV infusions (3 mg/kg; concurrent with HF10) were administered q3wk. AEs assessed per CTCAE 4.0. Tumor responses were assessed per mWHO and irRC at 12, 18, 24, 36 and 48 wks for patients (pts) continuing on HF10 monotherapy. Primary endpoint was Best Overall Response Rate (BORR) at 24 wks. Dose limiting toxicity (DLT) defined as greater than/= to G3 non-hematologic/hematologic toxicity, greater than/= G2 neurologic toxicity, or allergic event occurring within 1^st 3wks of therapy. Results: Of 46 pts enrolled and treated: 59% men, median age 67 yrs (range 28 to 91); disease stage 20% IIIB, 43% IIIC and 37% IV; 57% were treatment naïve and 43% with greater than/= to 1 prior cancer therapy for unresectable/metastatic melanoma. Most HF10-related AEs were less than/= to G2, similar to HF10 monotherapy. No DLTs were reported. 37% had greater than/= to G3 AEs, the majority due to ipi. HF10-related greater than/= to G3 AEs (n=3) were embolism, lymphedema, diarrhea, hypoglycemia, and groin pain. Of the 44 efficacy evaluable pts per irRC, BORR at 24 weeks was 41%; disease stability rate was 68%. As of Feb 06, 2017, median PFS was 19 months and median overall survival was 21.8 months. Conclusions: The combination HF10 and ipilimumab treatment demonstrated a favorable benefit/risk profile and encouraging antitumor activity in pts with stage IIIB, IIIC, or IV unresectable or metastatic melanoma. 

So...in this HF-10/ipi study - there were 46 patients, 63% of whom were Stage III and 37% Stage IV. About 1/2 were treatment naive and half had had at least one melanoma treatment.  Best ORR was 41%.  SD was attained in 68%.

********************************SD-101****************************

Here, SD-101, a different type of intralesional entirely, a TLR9 agonist from Dynavax, is paired with Pembro:

Phase 1b/2, open label, multicenter, study of intratumoral SD-101 in combination with pembrolizumab in anti-PD1 naïve and experienced metastatic melanoma patients.

ASCO 2017. J Clin Onco 35, 2017. Leung, Kummar, Agarwala, etal.

Background: SD-101 is a synthetic CpG-ODN agonist of TLR 9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Pembro is a PD-1 inhibitor approved for the treatment of metastatic melanoma. This study, MEL-01 assesses the safety and preliminary efficacy of SD-101 in combination with pembro in stage IIIC-IV melanoma. Methods: A modified 3+3 design was used for SD-101 dose escalation of 1, 2, 4, and 8 mg injected in a single tumor lesion Q1W x 4 then Q3W x 7 in combination with pembro (200 mg IV Q3W). Tumor responses were assessed per investigator using RECIST v1.1. Results: In phase Ib, 22 pts were enrolled: median age 64 y/o, male 68%, white 82%, Stage IV/IIIc 86%/14%, LDH greater than 1 ULN 27%, greater than/= to 3 prior lines therapy 36%, anti-PD-1 naïve (n = 9) and experienced (n = 13). There has been no dose limiting toxicity (DLT) to date. The most common (greater than/= to 20%) treatment-related AEs (TRAEs) were transient low-grade fatigue, myalgia, headache, chills and injection site reactions. Grade greater than/ = to3 TRAEs were observed in 59.1% pts (most common: myalgia 13.6% and injection site pain 13.6%). Immune-related AEs occurred in 2 pts. One had a G2 pneumonitis on Day 23 resulting in drug withdrawal and the other G3 hypophysitis (85 days after last treatment). No deaths occurred. Responses were observed at all doses in PD-1 inhibitor naïve pts, both at the injected and non-injected lesions. A response was seen at the 8 mg dose in PD-1 inhibitor experienced pts. With median f/u of 97 days (max 382), the ORR was 66.7% in the PD-1 inhibitor naïve patients with best overall response of CR 22.2% (n = 2), PR 44.4% (n = 4), SD 11.1% (n = 1), PD 11.1% (n = 1), and NE 11.1% (n = 1). In the PD-1 inhibitor experienced pts: PR 7.7% (n = 1) and SD 38.5% (n = 5). Conclusions: The combination of SD-101 and pembro was well tolerated and demonstrates no worsening of the expected toxicities of each of the individual monotherapies. These interim data support enhanced activity of adding SD-101 to pembro in anti-PD-1 naive metastatic melanoma as well as potential activity in anti-PD-1 experienced pts. 

Patients were Stage III/IV (14 and 86% respectively).  Of the 22, 9 were anti-PD-1 naive and 13 had already taken it.  SD-101 was injected into a single lesion and patients were also given pembro.  No matter the SD-101 dose, patients who had never had anti-PD1 before, all had a response in injected and non-injected lesions for an ORR of 66.7%, CR of 22%, PR of 44%, SD of 11%.  In patients who had had anti-PD-1 previously, there was a partial response in almost 8% and stable disease in 38%.
This is a very small sample.  

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Okay.  Why in the world we cannot have studies constructed in ways that make sense is beyond me!!! We KNOW the results of ipi alone...a 15-18% response rate is typical and that was borne out here. Why we cannot have a very simple study directly comparing T-VEC to CAVATAK to PV-10 and whatever other intralesionals there are on the market is nutters!  I have been calling for it for years....but clearly no one listens to me!  However, it seems that no matter the intralesional presented here....they all can kill the melanoma tumor they are injected into and other lesions hanging about the body elsewhere.  When used alone, CAVATAK and T-VEC studies report about a 28% ORR, while PV-10 has studies reporting a 50% ORR.  I don't have data on HF-10 and SD-101 when used alone. When used with ipi, HF-10, T-VEC, and CAVATAK boosted ipi's usual response rate of about 15% to about 40%. When SD-101 was paired with pembro (anti-PD-1), pembro's usual response rate of about 40% was boosted to 66%.  Why we are pairing these drugs with ipi is another huge question for me! Let's see....ipi has lower response rates and higher side effect risks than anti-PD-1....but I digress. As we have already learned in many other studies...treatment naive patients did better...but even those who had already been through the wringer did have a chance of a response. I still feel that intralesionals, whose side effects are pretty much limited to local redness and irritation at the injection site with some fever and fatigue, have a lot of promise and their effectiveness in getting rid of lesions that were NOT EVEN INJECTED should be able to teach us a great deal about how melanoma works and hides.  Pairing intralesionals with anti-PD-1 as well as radiation appears to be a treatment methodology that could clearly benefit many.

Hang in there ratties....and...thanks.  - c