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