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.  

**************************SUMMARY*************************
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

Happy Father's Day...to the BEST dad...for realz!!!

B has been the best dad....ALWAYS!!!

Dreaming up fun...

...and actively participating in it!

From making a little girl feel special when she gives him....ONE MORE pair of socks (though she was very sad she couldn't find pink ones!!!)...

...to making the kiddo's feel safe or adventurous - on a case by case basis!!

Not only sharing in the activities THEY enjoy....

...but... 

...even at the butt crack of dawn....

...FULLY....

...embracing them!!!!

The goofy....

...the colorful...

...and the serious ones!

Making technology a fun adventure...

Snow days play days....

Swimming where things might bite your dangly bits....

....and ever so many "fun" runs....were all taken in stride!!!!
So glad I was smart enough to pick the best dad ever for my critters. Happy father's day!  I love you ever so much, Bentie!!!! - les

Sew Chaotically! - Tale of 2 tops - Polly and Sally????

Taking an ASCO break today with a small moment of pretty....     Unlike some sewists (per their blogs and posts), I don't have much of a fabric "stash".....

This is all the fabric I have, apart from a basket of scraps that are literally pieces left over after making a garment from which I might find bits and pieces to use for pockets or trim of some sort, and often end up donating to a local teacher who thinks all kids should be able to sew on a button or hem their pants.  Clutter makes me a little crazy.  Plus, my early sewing adventures taught me that apart from basic skills that practice provides, choosing the perfect fabric for the garment is probably the most important part of creating an item that turns out well and you will love to wear.  I also learned in my Me Made May adventure that I needed a few more blouses to round out my closet.

To that end, I was excited to try out this little Polly Top, from By Hand - London.  I really like it.  As I noted in it's post, I used some left over bits and pieces, the center panel being some fabric thrifted from a sweater I no longer wore.  The curved insert gives it a pretty and unique shape while providing a nice replacement for a bust dart.

I am sure I will make it again, though I will probably raise the neckline in the back, as it is fairly low.  

Despite my personal limits on my "stash", sometimes a piece of fabric just demands to go home with me.  When stopping in at JoAnn's for some notions, the cutest grey blue seersucker with little red embroidered roses seemed essential!!!!  I bought all that was on the bolt.  Sadly, it was only a smidge over a yard. In keeping with meeting the needs of my wardrobe with more tops, I was hoping to make one utilizing a yoke that would feature the fabric arranged in a different direction from the rest of the garment.  But...there just wasn't enough material to go round.  Not deterred.....I put this top together using the New Look pattern which I've used several times for dresses, above, with the curved hem from the Polly top.

Ta dah.....

I lengthened the sleeves and kept the fit trim, but not so much so that a zip would be required.  The guts are pretty, too.  I used seam binding (rather than the flappy facings the pattern calls for) at the neck and hem.  The side seams are flat felled.  Arms are finished with the serger and hand hemmed.

For an old fella', at 18 years young, Karma still has his own stubborn opinions about where he's going!  Why DOES the Karm want to cross the road?????  18 years later, I still don't know!

On days when I am wheezy, have only a whispery voice (Thanks, little critters!!!), and am sick at heart....B can always lift my spirits and make me smile.  Thanks, buddy.

More from ASCO soon!  love, c

ASCO 2017: Antibody-drug conjugate (ADC) - Glembatumumab Vedotin in advanced melanoma

I have researched and written about ADC's (glembatumumab vedotin in particular) before.  Here are a couple of posts: Antibody-Drug Conjugate for melanoma

In 2013 I wrote:
"An ADC (antibody drug conjugate) is like a Trojan Horse!!!  It takes a bad ass cytotoxin, like auristatin (that's the one being used here), an anti-mitotic agent that derives its action by preventing tubulin polymerization and therefore stops cell division, attaches it via a special molecule to a monoclonal antibody that targets antigens preferentially expressed on the surface of the targeted cancer cells..in this case, Endothelin B.  This method allows patients to survive being treated with really toxic agents without suffering the terrible side effects that would certainly ensue should those cytotoxins be injected directly.  By taking them under cover, only the bad cells we want to target are damaged."

"ADC's have been in the works since the 80's. Over that time laboratory researchers have found many more possible antibodies to use (and studied which tumors express them the most) and a variety of gradually improving techniques to "link" the chemotherapeutic agent to the antibody. Improved "linkers" seem to have made it easier to use a variety of antibodies as well as cytotoxic agents while keeping the whole little trifecta intact until it reaches its destination.  Patent information seems to indicate that researchers feel they may even be able to target infectious organisms in the future.  Two ADC's have been marketed for lymphoma and leukemia.  And, just a couple of weeks ago, Celldex got FDA approval for CDX-011 (glembatumumab vedotin) as a treatment for Her-2 breast cancer.  Interestingly, initially, this drug which uses "auristatin conjugated to a monoclonal antibody that recognizes GPNMB, expressed at higher levels in melanoma and breast tumors"  was tested in patients with melanoma as well as breast cancer.  Sievers and Senter, in a Seattle Genentech report state, "In a phase I/II trial in patients with unresectable late-stage melanoma, CDX-011 showed overall response rates ranging from 14% to 19% depending on dosing frequency and GPNMB expression levels."  However, at this point, it seems that this particular ADC is no longer being utilized in melanoma trials."

Now there is this...looking at CDX011-05 ~ 

A phase II study of glembatumumab vedotin (GV), an antibody-drug conjugate (ADC) targeting gpNMB, in advanced melanoma.

ASCO 2017. J Clin Oncol 35, 2017. Ott, Pavlick, Johnson,...Infante, Luke, ...Hamid.

Background: gpNMB is an internalizable transmembrane glycoprotein expressed in melanoma and multiple other tumor types. The ADC GV (CDX-011) delivers the potent cytotoxin MMAE to gpNMB+ cells. GV has shown promising activity in advanced melanoma and breast cancer. Methods: This Phase II study (CDX011-05) assessed the efficacy and safety of GV monotherapy (1.9 mg/kg q3w) for patients (pts) with advanced melanoma progressive after less than/= to 1 chemotherapy, greater than/= to 1 checkpoint inhibitor (CPI) and if BRAF^V600mutated, greater than/= to 1 BRAF/MEK inhibitor. Central IHC determined gpNMB expression in archival and/or pre-treatment tumor. Primary endpoint was objective response rate (ORR) (RECIST 1.1) with greater than/ = to 6 responders out of 52 evaluable pts as threshold for antitumor activity. Additional endpoints: progression free survival (PFS), overall survival (OS), duration of response (DOR), safety, PK/PD and correlation of tumor gpNMB expression with efficacy. Results: 62 pts enrolled (all evaluable) had median age of 67 years; 55% male; 21% BRAF^V600mutated; 63% with greater than/= to 3 lines prior therapy; 100% had prior CPI; 100% Stage IV; 89% M1c. One confirmed complete response (CR) and 6 confirmed partial responses (PR, including 1 unconfirmed CR) were seen (confirmed ORR = 11%); 33 pts had stable disease including 3 unconfirmed PR. Median DOR = 6.0 (range: 4.1, 14+) months (mos), median PFS = 4.3 mos and median OS = 9.8 mos; 26 pts continue to be followed for survival. All pts with available tissue (60/60) had gpNMB+ tumors; 47/60 had 100% gpNMB+ epithelial cells; no clear correlation with outcome was seen in this population with consistent high expression. Toxicities included alopecia, neuropathy, rash, fatigue and neutropenia. Treatment-related rash in cycle 1 was associated with improved ORR (rash = 22%; no rash = 7%), PFS and OS. Conclusions: GV has promising activity (primary endpoint of ORR was met) with a manageable safety profile in heavily pre-treated melanoma pts. Additional cohorts evaluating GV with either varlilumab, an activating anti-CD27 monoclonal antibody, or PD-1 inhibitors are open to accrual to provide further insights into the synergy of ADC and immunotherapy. Clinical trial information: NCT02302339

Hmmm....  Here we go:  First off, it is not clear to me why they are now calling the drug "CDX011-05".  A new name implies that it is different in some way...but the difference (if there is one) is not clarified here.  At any rate ~ in this Phase II study, 62 patients, all with stage IV melanoma, 21% with BRAF V600 mutation, 63% having undergone 3 or more prior treatment regimens, were enrolled.  There was one complete response and 6 partial responses for a total ORR of 11%.  33 patients had stable disease. Toxicities were what we have come to expect with this ADC:  alopecia, neuropathy, rash, fatigue, and neutropenia.  One interesting note was that those who developed a rash in the first cycle had an improved response.  Also interesting is the fact that the studies I addressed in the 2013 post with "CDX011" touted ORR of 14 and 19%.

Not sure about the future of this therapy.  They really need to work on making the "link" stronger so that there is less leakage of the chemo that leads to much of the side effects.  Perhaps that is what they tried to do in the CDX011-05 version...don't know.  Also not sure about a decreased ORR in this study compared to the previous.  However, I will be forever grateful to this therapy for keeping one of my dearest ones around for a year more, giving him time to find a therapy that worked better for him in the end.

This one's for my dear J and F!!!! love, c

ASCO 2017: Atezo (anti-PDL1) with Cobimetinib (MEKi) and Vemurafenib (BRAFi) for BRAF V-600 melanoma

In 2016 several reports came out and studies started looking at combining immunotherapy with BRAF/MEK.  Here's one report with a link within:  The whole she bang - immunotherapy with BRAF/MEK for melanoma

Per the researchers, the theoretical benefit of the triple whammy is this:
"Immunotherapy of advanced melanoma with CTLA-4 or PD-1/PD-L1 checkpoint blockade induces in a proportion of patients long durable responses. In contrast, targeting the MAPK-pathway by selective BRAF and MEK inhibitors induces high response rates, but most patients relapse. Combining targeted therapy with immunotherapy is proposed to improve the long-term outcomes of patients."

Here is a post from ASCO of last year:  Anti-PD1/PDL1 combined with BRAFi in BRAF+ patients

Part of that post notes a trial in which atezolizumab (an anti-PD-L1 monoclonal antibody, also called Tecentriq) was dosed with vemurafenib (a BRAF inhibitor) like this:
1.  atezo and vemurafenib together = ORR of 33%
2.  Vemurafenib X 56 days followed by atezo = ORR of 75%
3.  Vemurafenib X 28 days followed by atezo = ORR 100%

Here atezo is combined with cobimetinib (a MEKi) and vemurafenib:   

Atezolizumab (A) + cobimetinib (C) + vemurafenib (V) in BRAF^V600-mutant metastatic melanoma (mel): Updated safety and clinical activity.

ASCO 2017. J Clin Oncol 35, 2017. Sullivan, Gonzalez, Lewis, Hamid, Infante, ...Hodi, ...et al.
Background: Targeted inhibition of MEK with C and BRAF with V in BRAF^V600-mutant mel can lead to both anticancer immune activation and direct tumor cell death. A, an anti–PD-L1 monoclonal antibody, inhibits PD-L1/PD-1 signaling. Combining C + V with A may enhance antitumor activity, potentially leading to improved clinical responses and durability. Preliminary data from this phase Ib study showed that A + C + V had a manageable safety profile and promising antitumor activity in patients (pts) with untreated BRAF^V600-mutant unresectable/metastatic mel, with increases in CD8-positive T-cell infiltration observed after C + V. We present updated safety and efficacy data. Methods: Pts received A + C + V after a 28-day run-in with C + V. A was given at 800 mg q2w, C at 60 mg qd for the first 21 days of each 28-day cycle, and V at 960 mg bid during day 1–21 of run-in and 720 mg thereafter. Safety was evaluated in pts who had ≥1 dose of A; efficacy, in pts who had greater than/= to1 dose of A by the data cutoff date and received greater than/= to 1 dose of A, C, or V by the dosed-by date. Results: Thirty-four patients were treated and evaluated for both safety and efficacy. Median survival follow-up was 7.1 months (range 2.5–19.9). Elevated AST/ALT, diarrhea, arthralgia, fatigue, photosensitivity, pyrexia, nausea, flu-like symptoms, maculopapular rash, and pruritus were reported as A- and/or C- and/or V-related in and 20% of pts at any grade (G). A/C/V-related G3–4 adverse events (AEs) were seen in 15 pts (44.1%) with the triple combination (none G5). Three serious AEs were A-related. All AEs were manageable and reversible. Elevated ALT/AST (three pts each) and rash (one pt) led to discontinuation of any drug. Unconfirmed RECIST V1.1 responses were observed in 29 pts (85.3%; six complete, 23 partial). Three pts with confirmed partial responses had resolution of target lesions. Twenty of the 29 responding patients continue to respond at the time of the data cutoff. Conclusions: Updated results confirm preliminary findings that A + C + V has a manageable safety profile and promising antitumor activity in pts with BRAF^V600-mutant metastatic mel. Continued exploration of A + C + V is warranted. Clinical trial information: NCT01656642  

This trial was really just to assess dosage and safety.  However - 34 patients with BRAF V600 mutated melanoma were treated with the BRAF/MEK combo for 28 days and then atezo was added q 2 wks while the MEKi was continued once daily for the first 21 days of each 28 d cycle and BRAFi was given in the same way, though twice a day and at a decreased dose than had been given in the initial treatment cycle.  Side effects were as expected for these drugs and all reversible, though 4 patients had to discontinue their use.  Unconfirmed (????  don't know why they were unconfirmed!!!) responses were found in 29 patients. 6 patiens had a complete response and 23 had a partial.  Three of those with partial responses had resolution of their target lesions.  20 of the 29 responders were still responding at data cutoff...though how long that was is not clearly delineated in the abstract.

So...one more bit of hope for ratties.  Granted 1/2 of melanoma patients (those who are not BRAF+) remain unaddressed with this approach.  But - step by step. - c

ASCO 2017: ERK inhibitor - Ulixertinib (BVD-523) working in NRAS as well as BRAF V600 and non-V600 melanoma

Many "innovative" combinations that would make targeted therapy better have long been discussed, including: Hsp90,   HDAC,   PI3 kinase/AKT,   ERK, and   ERBb3 inhibitors and then some.  Data is more readily available on some than others.  Keeping the diagram posted yesterday in mind...as well as this one:

 Here is a report on Ulixertinib, an ERK inhibitor:

First-in-class oral ERK1/2 inhibitor Ulixertinib (BVD-523) in patients with advanced solid tumors: Final results of a phase I dose escalation and expansion study.

ASCO 2017. J Clin Oncol 35, 2017. Li, Janku, Patel, ...Flaherty, ...Sznol, Sosman..., Ribas, ….Infante.

Backkground: Aberrant MAPK pathway activation is known to be an oncogenic driver in many solid tumors, making ERK inhibition an attractive therapeutic strategy. Ulixertinib is an oral ERK1/2 inhibitor that demonstrated potent activity in vitro and tumor regression in BRAF and RAS mutant xenograft models. Methods: This multi-center phase I trial enrolled patients (pts) with advanced solid tumors. Dose escalation utilized an accelerated 3+3 design; expansion cohorts included BRAF or NRAS mutant melanoma and other BRAF or MEK mutant cancers. Study objectives were to characterize dose limiting toxicities (DLTs), maximum tolerated dose (MTD), toxicity profile, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity by RECIST 1.1. Results: A total of 135 pts were enrolled. Dose escalation enrolled 27 pts (10-900 mg BID) and established the MTD and recommended phase 2 dose (RP2D) of 600 mg BID. DLTs included rash, diarrhea, elevated AST, and elevated creatinine. Drug exposure was dose proportional up to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108 pt expansion cohort, there were no drug related deaths; however, 32% of pts required a dose reduction. The most common adverse events were rash (49%), diarrhea (47%), fatigue (41%), and nausea (37%). In addition to 3 pts with partial responses during escalation (11%), an additional 9 of 83 (11%) evaluable pts at expansion had a partial response: 1 melanoma pt refractory to prior BRAFi/MEKi treatment, 3 NRAS mutant melanoma pts, 2 pts with BRAF V600E mutant lung cancers including response in brain metastases, 1 with BRAF V600E mutant glioblastoma multiforme, 1 with BRAF G469A head and neck cancer, and 1 with BRAFL485W gallbladder cancer. The duration of response ranged from 2 to 24+ months. Conclusions: Ulixertinib at 600 mg twice a day has an acceptable safety profile and has produced durable responses in pts with NRAS mutant melanoma, BRAF V600 and non-V600 mutant solid tumors including melanoma, glioblastoma multiforme, lung cancers with brain metastases, gallbladder and head and neck cancers. These data support further clinical development of ulixertinib. Clinical trial information: NCT01781429

Despite a lot of back and forth about cohorts and expansion cohorts....as best as I can tell, 108 patients with various sold tumors, took ulixertinib, 600 mg orally, twice daily.  Most common side effects were rash, diarrhea, fatigue and nausea...no drug related deaths, though 32% required a drug reduction.  Of 83 evaluable patients, 9 had a partial response.  Three of these were NRAS mutant melanoma and 4 had tumors that were BRAF V600E mutant, but only one of those had melanoma and they had been refractory to prior BRAFi/MEKi treatment.  

So...incredibly small numbers period...especially in regard to melanoma...but...you gotta start somewhere!!!  Hang in there ratties. - c