Reviews of T-VEC in melanoma patients: alone, with ipi or with pembrolizumab ~

I have been a fan of intraleional (also referred to as intratumoral) treatment - therapies that are injected directly into melanoma lesions - for a long time.  Here are a bazillion reports: Intralesional therapies for melanoma

While T-VEC is currently the only version with FDA approval, here is a list of some of the drugs most often used:
CAVATAK - derived from the Coxsackievirus
T-VEC - also called OncoVEX, Imlygic,  or Talimogene Laherparepvec - uses the herpes virus with GM-CSF
PV-10 - derived from Rose Bengal
HF10 - also derived from HSV
SD101 - a TLR9 agonist
IL-2 -  is also being used

Now this -

Patterns of response with talimogene laherparepvec in combination with ipilimumab or ipilimumab alone in metastatic unresectable melanoma.  Chesney, Puzanov, Collichio, et al. Br J Cancer. 2019 Jul 29. 

Talimogene laherparepvec (T-VEC) has demonstrated efficacy for unresectable melanoma. We explored response patterns from a phase 2 study evaluating patients with unresectable stage IIIB-IVM1c malignant melanoma who received T-VEC plus ipilimumab or ipilimumab alone. Patients with objective response per modified irRC were evaluated for pseudo-progression (single greater than/= to 25% increase in tumour burden before response). Patients without pseudo-progression were classified by whether they responded within or after 6 months of treatment start; those with pseudo-progression were classified by whether pseudo-progression was due to increase in existing lesions or development of new lesions. Overall, 39% (n = 38/98) in the combination arm and 18% (n = 18/100) in the ipilimumab arm had an objective response. Eight responders (combination, n = 7; ipilimumab, n = 1) had pseudo-progression; most occurred by week 12 and were caused by an increase in existing lesions. These data reinforce use of T-VEC through initial progression when combined with checkpoint inhibitors.

We already have this report from 2017:  T-VEC plus ipi vs ipi alone ~ along with additional T-VEC data...  where it is noted that:  "...quite promising is the combination of talimogene laherparepvec and pembrolizumab. In the phase IB ­MASTERKEY-265 trial of 21 previously untreated patients, responses were seen in 57% of patients, including complete responses in 7 patients, with no dose-limiting toxicities.⁹ This regimen is now in phase III trials."...

Now, this -

Response to the Rechallenge With Talimogene Laherparepvec (T-VEC) After Ipilimumab/Nivolumab Treatment in Patient With Cutaneous Malignant Melanoma Who Initially Had a Progression on T-VEC With Pembrolizumab.  Afzal, Shirai.  J Immunother. 2019 Mar 29.   Talimogene laherparepvec (T-VEC) is approved for unresected stage III-IV malignant melanoma. T-VEC has a direct cytotoxic effect and enhances the antitumor immunity of host cells. Immune checkpoints inhibitors also enhance the immunity of host cells by increasing the recruitment of antigen-presenting cells or activation and restoration of T-cell functions. Both type of therapies can potentiate the effect of the other therapy. We are reporting a case of T-VEC rechallenge who initially progressed on T-VEC with pembrolizumab but then responded to T-VEC rechallenge after intervening ipilimumab/nivolumab. An 83-year-old man developed a subungual lesion of the left thumb and found to have AJCC V. 7 stage IIIb melanoma. Few months later, he developed axillary lymphadenopathy and multiple subcutaneous nodules (AJCC V. 7 stage IIIc). The patient was started on intralesional rose Bengal and pembrolizumab. After 4 cycles of pembrolizumab with rose Bengal, a positron-emission tomography/computerized tomography scan showed the progression of disease. He was started on T-VEC intralesional injections with concurrent pembrolizumab, however, after 3 T-VEC injections and 2 more cycles of pembrolizumab, there was the progression of disease. Subsequently, ipilimumab/nivolumab was started and patient responded partially. Ipilimumab/nivolumab was held due to toxicity. Eight weeks from the last dose of ipilimumab/nivolumab, he experienced locoregional progression and was rechallenged with T-VEC monotherapy. The patient showed a significant response after second T-VEC injection and continued to show response 6 months since rechallenge. After, initial progression on T-VEC with pembrolizumab, intervening immune checkpoints inhibitors may favorably modify the antitumor immunity and potentiate antitumor effect of T-VEC rechallenge.

Cases like this are so difficult to understand - by the patient - poor soul, mostly - but also:  Did the rechallenge with T-VEC really turn the tide?  Or - did all the other therapies - or ONE of the other therapies - finally kick in and just needed more time to work?  We really can't say.  Patients who have experienced multiple therapies and then finally respond, hold the key to many questions.  I'm just not sure we know what exactly they unlock.

Then, this -

Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma.  Andtbacka Collichio, Harrington, et al.  J Immunother Cancer. 2019 Jun 6.

Talimogene laherparepvec is an oncolytic immunotherapy approved in the US, Europe, Australia and Switzerland. We report the final planned analysis of OPTiM, a randomized open-label phase III trial in patients with unresectable stage IIIB-IVM1c melanoma.

Patients were randomized 2:1 to receive intratumoral talimogene laherparepvec or subcutaneous recombinant GM-CSF. In addition to overall survival (OS), durable response rate (DRR), objective response rate (ORR), complete responses (CR), and safety are also reported. All final analyses are considered to be descriptive and treatment responses were assessed by the investigators.

Of 436 patients in the intent-to-treat population, 295 were allocated to talimogene laherparepvec and 141 to GM-CSF. Median follow-up in the final OS analysis was 49 months. Median OS was 23.3 months (19.5-29.6) and 18.9 months (16.0-23.7) in the talimogene laherparepvec and GM-CSF arms, respectively . DRR was 19.0 and 1.4%; ORR was 31.5 and 6.4%. Fifty (16.9%) and 1 (0.7%) patient in the talimogene laherparepvec and GM-CSF arms, respectively, achieved CR. In talimogene laherparepvec-treated patients, median time to CR was 8.6 months; median CR duration was not reached. Among patients with a CR, 88.5% were estimated to survive at a 5-year landmark analysis. Talimogene laherparepvec efficacy was more pronounced in stage IIIB-IVM1a melanoma as already described in the primary analysis. The safety reporting was consistent with the primary OPTiM analysis.

In this final planned OPTiM analysis, talimogene laherparepvec continued to result in improved longer-term efficacy versus GM-CSF and remained well tolerated. The final analysis also confirms that talimogene laherparepvec was associated with durable CRs that were associated with prolonged survival.

This is one of those studies that gets on my nerve.  We wouldn't have expected GM-CSF to do much better than it did!!!!  But, I guess it shows what T-VEC can do on its own.

And finally, this:

Intratumoral Immunotherapy-Update. Hamid, Ismail, Puzanov.  Oncologist.  2019 Nov 29.

Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T-VEC), a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T-VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting greater than/= to6 months) over subcutaneous GM-CSF (16.3% vs. 2.1%). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T-VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T-VEC in the treatment of advanced melanoma as a model for future solid tumor indications.

IMPLICATIONS FOR PRACTICE: This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T-VEC is the only U.S. Food and Drug Administration (FDA)-approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T-VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

For those interested, here's a direct link to the abstract above:  Intratumoral Immunotherapy-Update 2019.

So - there you have it. NOW!!!  We need direct head-to-head comparisons of some of these other intralesionals (PV-10, CAVATAK, etc.) to T-VEC.  I also think it is clear that generally, intralesional therapy COMBINED with anti-PD-1 is the way to go - whether you are Stage III or IV.   But, that's just me...

Thanks, ratties.  You change the world! - c

ASCO 2015 - intralesional therapy for melanoma

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

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

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

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

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

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

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

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

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

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

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

Another recent intralesional therapy report, but NOT from ASCO:

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

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

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

ASCO 2016 - T-VEC: Talimogene laherparepvec (previously - OncoVEX GM-CSF) - now - with pembro and still enrolling!

Back in 2014, within a discussion with Ribas regarding ASCO 2014 reports, Weber said this:  "....Injectable therapies are making a comeback.....eons ago we were injecting BCG, interferon, and IL-2 into local-regional melanoma metastasis.....now there are some interesting drugs, and T-VEC is one of them.  I see this as a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipi, or a combination of those....that's where I see intralesional therapy going."

I have put together many posts regarding T-VEC....this one recently:  T-VEC: more good news...local and systemic responses

To review ~ my previous review:   Talimogene laherparepvec [now T-VEC] (originally called OncoVex GM-CSF) is.....  "....here's my best interpretation of what it all means.  First of all, let's back up a step!  Yes, the magical "sargramostim" is the same thing as GM-CSF, leukine and used in OncoVex.  It is an immunostimulator used most often to help grow new white cells after a bone marrow transplant or when they have been depleted by conventional chemo in diseases like leukemia."

OR....here's what I noted before in a post about the intralesional therapy OncoVEX: 

  "OncoVEX is a 2nd generation herpes virus embedded with GM-CSF...a substance that causes the body to make more white cells. (GM-CSF can be given to premature babies and leukemia patients with low white cell counts to help build them back up....and reverse immune suppression.) But, in OncoVEX, it is thought to only replicate in the tumor cells.  The white cells produced in the process kill off the tumor cells.  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 are the new reports from ASCO....and this TVEC/Pembro trial is still enrolling, y'all!!!

A phase 1/3 multicenter trial of talimogene laherparepvec in combination with pembrolizumab for unresected, stage IIIB-IV melanoma (MASTERKEY-265).  ASCO 2016, #TPS9598.  J Clin Oncol 34, 2016.  Long, Drummer, Ribas, Puzanov, et al.

Background: Talimogene laherparepvec, an oncolytic viral immunotherapy, was designed to selectively replicate in tumors resulting in lytic cell death, antigen release, and production of GM-CSF to enhance systemic antitumor immune responses. Talimogene laherparepvec improved durable response rate vs GM-CSF in unresectable stage IIIB-IV melanoma. Pembrolizumab, a human programmed death receptor-blocking antibody approved for the treatment of advanced melanoma, improved PFS and OS vs ipilimumab in patients (pts) with stage III-IV melanoma. Combining talimogene laherparepvec + pembrolizumab may further enhance antitumor immune responses. Here we describe the phase 3 design of a phase 1b/3 double-blind, placebo-controlled study assessing the safety and efficacy of talimogene laherparepvec + pembrolizumab in unresected stage IIIB-IV melanoma. Phase 1b enrolled 21 pts treated with talimogene laherparepvec + pembrolizumab. No dose limiting toxicities were observed (primary endpoint), and preliminary responses were observed in 9 of 16 evaluable pts with median tumor follow-up of 17 weeks (Long et al, SMR 2016). Methods: Approximately 660 pts will receive pembrolizumab + placebo or pembrolizumab + talimogene laherparepvec (1:1 randomization). Co-primary endpoints: PFS and OS. Key secondary endpoints: adverse events and response-based endpoints. Key eligibility criteria: unresectable stage IIIB-IV melanoma naïve to systemic treatment except up to one prior line of BRAF inhibitor-based treatment, measurable and injectable lesions, ECOG PS 0-1, no active cerebral metastases, no autoimmunity/immunosuppression, no active herpetic infection. Talimogene laherparepvec (10⁶ PFU/mL first dose, 10⁸ PFU/mL subsequent doses) or placebo is injected into cutaneous or nodal lesions on day 1, weeks 0, 3, 5, 7 then q3w starting day 1 week 9. Pembrolizumab 200 mg IV is given q3w starting day 1 week 0. Treatment continues until confirmed complete response or progressive disease, intolerance, up to 2 years, or for talimogene laherparepvec or placebo, when there are no longer injectable lesions. Clinical trial information: NCT02263508

Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma.  ASCO 2016. #9568.  J Clin Oncol 2016.  Authors as above.

Background: T-VEC is a herpes simplex virus (HSV)-1 -based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF and stimulate antitumor immune responses in melanoma. T-VEC significantly improved durable response rate vs GM-CSF in stage IIIB-IV melanoma patients (pts) with injectable tumors. Pembro inhibits programmed cell death protein 1 and improves survival in advanced melanoma. The combination may further improve clinical benefit. Here we report phase 1b efficacy, safety and biomarker data from a phase 1b/3 study of T-VEC+pembro in unresectable stage IIIB-IV melanoma with all pts having started on T-VEC+pembro greater than or = to, 6 mo prior. Methods: Key inclusion criteria: unresectable stage IIIB-IV melanoma, injectable lesions; no prior systemic tx; and ECOG PS 0-1. T-VEC: ≤ 4 mL in (sub)cutaneous/nodal lesions, 10⁶ PFU/mL d1, 10⁸PFU/mL d22 then Q2W; pembro: IV, 200 mg d36 then Q2W. Tx until first occurrence of: complete response (CR); no injectable tumors (for T-VEC); confirmed PD per modified immune-related response criteria (irRC); tx intolerance; 24 mo of pembro. T cell subsets were evaluated by flow cytometry at baseline, during T-VEC alone, and during combination. Results: 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. Circulating CD8+ T cells including those expressing defined immune modulatory receptors (eg Tim3, BTLA) became elevated during tx with T-VEC initially but decreased after pembro began on d 36. Conclusions: The combination of T-VEC+pembro was associated with clinical benefit in advanced melanoma, as assessed by ORR and CR rate. A randomized, double-blind phase 3 trial of T-VEC+pembro vs T-VEC placebo+pembro is under way. Updated clinical and biomarker data will be presented at the meeting. Clinical trial information: NCT02263508

Way to rock it, ratties.  - c 

Intralesionals for melanoma - some new reports

I was a fan of intralesional therapies for melanoma long before they were used with any frequency in real live melanoma peeps! I first posted about Rose Bengal (the name I much prefer to the current PV-10) in 2012!!  Rose Bengal sustains high response rate in Melanoma patients!!!  These days the medications used intralesionally for melanoma patients has grown.  Even this list isn't comprehensive:

CAVATAK - derived from the Coxsackievirus
T-VEC - also called OncoVEX, Imlygic,  or Talimogene Laherparepvec - uses the herpes virus with GM-CSF
PV-10 - derived from Rose Bengal
HF10 - also derived from HSV
SD101 - a TLR9 agonist
IL-2 and IL-12 (tavo) -  are also being used

This link, including an update from June of this year, will give you - A zillion more posts on all things intralesional  Now, there are these ~

False positive FDG uptake in melanoma patients treated with talimogene laherparepvec (T-VEC).  Mulder, Stahlie, Verver, et al.  J Surg Oncol.  Jul 2021.

Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy and has been approved for the local treatment of unresectable (stage IIIB/C and IVM1a) cutaneous melanoma. During T-VEC treatment, tumor response is often evaluated using [18F]2-fluoro-2-deoxy- d-glucose(FDG) positron emission tomography/computed tomography (PET/CT). In a Dutch cohort (n = 173), almost one-third of patients developed new-onset FDG uptake in uninjected locoregional lymph nodes during T-VEC. In 36 out of 53 (68%) patients with new nodal FDG uptake, nuclear medicine physicians classified this FDG uptake as "suspected metastases" without clinical or pathological confirmation in the majority of patients. These false positive results indicate that new-onset FDG uptake in locoregional lymph nodes during T-VEC treatment does not necessarily reflect progressive disease, but may be associated with immune infiltration. In current clinical practice, physicians should be aware of the high false positive rate of FDG uptake during treatment with T-VEC in patients with melanoma. Therefore, pathological examination of lymph node lesions with new FDG uptake is recommended to differentiate between progressive disease and immune infiltration after treatment with T-VEC.

Given the real (and wonderful) possibility of "by-stander response" - ie the positive response in lesions NOT injected when intralesional therapy is used - why oh why would you assume that uptake visible on scans is progression you silly silly radiology peeps???!!!!  Live and learn people!  Live and learn!

Durability of Complete Response to Intralesional Interleukin-2 for In-Transit Melanoma.  Khoury, Knapp, Fyfe, et al.  J Cutan Med Surg.  Jul-Aug 2021.

Background: Intralesional injection of interleukin-2 (IL-2) for in-transit melanoma (ITM) is associated with a high rate of complete response. However, there is a paucity of data on treatment durability and long-term outcomes.

Methods: Consecutive patients with ITM, treated with intralesional IL-2 therapy, at the Tom Baker Cancer Center were identified from April 2009 to August 2019. All patients received at least 4 cycles (every 2 weeks) of IL-2 (5 MIU/mL). Complete response was defined as sustained (ie, 3 months) clinical complete remission of all known in-transit disease.

Results: Sixty-five patients were treated with curative intent for in-transit disease with intralesional IL-2. Complete clinical response was identified in 44.6% (29/65). In this subset of patients, the median number of lesions per patient was 9 (range 1-40). The median total dose of IL-2 was 0.8 mL (IQR 0.4-1.5) per lesion. One patient received isolated limb infusion and 13.8% (4/29) received systemic immunotherapy as part of their initial management. At a median follow-up of 27 months (IQR 16-59), 34.5% (10/29) developed recurrent disease. Of these patients, 50.0% (5/10) presented with synchronous in-transit and distant metastases. The median time to recurrence was 10.5 months (IQR 5.8-16.3).

Conclusion: With long-term follow-up, 65.5% of complete responders have a durable response to intralesional IL-2 therapy. In this cohort of patients, local in-transit recurrence is most likely to occur within 12 months and is often associated with concomitant distant disease.

Treatment of in-transit melanoma metastases using intralesional PV-10.  Thompson, Saw, Dalton, et al.  Melanoma Res.  June 2021.

Melanoma in-transit metastases (ITMs) can sometimes be difficult to manage by surgical excision due to their number, size or location. Treatment by intralesional injection of PV-10, a 10% solution of rose bengal, has been reported to be a simple, safe and effective alternative, but more outcome data are required to confirm its value in the management of ITMs. Two hundred and twenty-six melanoma ITMs in 48 patients were treated with intralesional PV-10 supplied under a special-access scheme. By 8 weeks a complete response in all injected ITMs was achieved in 22 patients (46%) and a partial response in 19 patients (40%). Of 19 patients who had uninjected metastases, 3 (16%) had a response in these. The most common adverse event was transient localised pain in injected tumours. New ITMs developed in 25 patients within 8 weeks, and later in another 8 patients. Repeat injection cycles were given to 21 patients: 13 of these received repeat injection into partially responding or nonresponding tumours, 5 had new ITMs, as well as partially-responding lesions injected, and 3 received injection into new ITMs only. Twenty-two patients received subsequent systemic therapy. At 1 year 37 of the 48 patients were alive, 28 with melanoma, and at 2 years 27 were alive, and 19 with melanoma. Injection of PV-10 was simple and safe and resulted in tumour involution in most patients and sometimes in noninjected tumours. However, many patients developed new lesions; these were treated by further PV-10 injections or with alternative therapies.

T-VEC for stage IIIB-IVM1a melanoma achieves high rates of complete and durable responses and is associated with tumor load: a clinical prediction model.  Stahlie, Franke, Zuur, et al.  Cancer Immunol Immunother.  August 2021.

Background: Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous and nodal melanoma lesions in stage IIIB-IVM1a patients. This study set out to identify prognostic factors for achieving a complete response that can be used to optimize patient selection for T-VEC monotherapy.

Methods: Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016-12 and 2020-01 with a follow-up time greater than 6 months, were included. Data were collected on baseline characteristics, responses and adverse events (AEs). Uni- and multivariable analyses were conducted, and a prediction model was developed to identify prognostic factors associated with CR.

Results: A total of 93 patients were included with a median age of 69 years, median follow-up time was 16.6 months. As best response, 58 patients (62%) had a CR, and the overall response rate was 79%. The durable response rate (objective response lasting greater than 6 months) was 51%. Grade 1-2 AEs occurred in almost every patient. Tumor size, type of metastases, prior treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving CR. The prediction model includes the predictors tumor size, type of metastases and number of lesions.

Conclusions: This study shows that intralesional T-VEC monotherapy is able to achieve high complete and durable responses. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting use earlier in the course of the disease.

Much like every other treatment in the melanoma arsenal, intralesional therapy (no matter the type you choose) is not a 100% cure nirvana.  Still, to my mind, it is a valuable weapon available to melanoma patients with in-transit lesions and as a supplement to Stage III and IV patients being treated simultaneously with systemic therapy.  As ever, those with the lowest tumor burden do best.  And sadly, nobody does the Even Steven clinical trials I want to see, placing similar patients on the various intralesionals - with and without equivalent systemic therapies - and THEN comparing outcomes!!!!  Why not, oh brilliant researchers?  WHY?????

For what it's worth - c

T-VEC plus ipi vs ipi alone ~ along with additional T-VEC data...

I've been posting updates about T-VEC since 2015.  Put 'T-VEC' in the search bubble and you will find a zillion articles.  Here's one from ASCO of this year, covering intralesional/intratumoral therapies generally and T-VEC in particular:  ASCO 2017: All things intralesional/intratumoral

Now there's this:

Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma. Chesney, Ppuzanov, Collichio...Hamid...Lebe...Andtbacka, Kaufman.  J Clin Oncol. 2017 Oct 5.

We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. 

Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, less than/= to 4 mL × 10⁶ plaque-forming units/mL; after 3 weeks, less than/= to 4 mL × 10⁸ plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. 

One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone( n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response. Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade greater than/= to 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Patients with the ipi/T-VEC arm certainly did better than ipi alone.  In this post: The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down -  From the interview the post covers, Dr. Weber notes:

Checkpoint Inhibition Plus Talimogene Laherparepvec
The injectable oncolytic virus talimogene laherparepvec may prove to be a much better therapeutic when paired with a checkpoint inhibitor, vs its solo use, Dr. Weber said. “If you can inject enough tumors with enough volume, I think you will begin to turn cold tumors into hot tumors, and you could follow this with checkpoint inhibition,” he explained.

The combination of ipilimumab and talimogene laherparepvec doubled the response rate over ipilimumab alone, in a study in which even patients with visceral disease (not directly injected) experienced significant responses.⁸ “This looks very promising. Only time will tell whether we see a very good duration of response,” he commented.

Also quite promising is the combination of talimogene laherparepvec and pembrolizumab. In the phase IB ­MASTERKEY-265 trial of 21 previously untreated patients, responses were seen in 57% of patients, including complete responses in 7 patients, with no dose-limiting toxicities.⁹ This regimen is now in phase III trials.

To that last point...combining T-VEC with anti-PD-1 may be even better than combining it with ipi with far fewer side effects:  T-VEC (Talimogene laherparepvec, Imlygic...whatever you want to call it) - oncolytic virotherapy may improve the efficacy of anti-PD-1 by changing the tumor microenvironment!!

One more personal report I can share ~ If you read the first report carefully, you will see that among side effects, researchers note  "chills (combination, 53%; ipilimumab alone, 3%)".  Clearly, if "chills" occur at a rate of 53% with T-VEC plus ipi and only at 3% with ipi alone...the "chills" are due to T-VEC!!!  A dear one of mine is currently taking pembro (Keytruda...an anti-PD-1 product) with T-VEC and tells me that he has been dealing with significant fevers.  Which of course would be the case, if a researcher reports "chills"!!!  Isn't it interesting how folks who are NOT experiencing the side effects report them??????

Thanks for sharing and being an awesome rattie, Mark!!!  Hang tough, the rest of you ratties out there!!! - c

Intratumoral or Intralesional therapy for melanoma - again. Yep, AGAIN!!! ASCO 2021, here we go!

Intralesional (intratumoral) therapies have come a loooooong way, baby!  I first began reporting on them in 2014.  Here's a link to a zillion articles and posts:  More than you ever wanted to know about intralesional therapy for melanoma! 

As I embark on posting the things I feel are important from ASCO this year, I will add articles I have been collecting on each topic.  We will start here, with all things intralesional ~ 

The following link takes you to a pretty good review of current state of the data regarding intralesional therapy.  PV-10, Toll-like receptor agonists (TLR's), Intratumoral oncolytic viruses - to include:  CAVATAK, Pexastimogene Devacirepvec (Pexa-Vec), HF10, PVS-RIPO, and TVEC are covered.  Lots of interesting charts and trial results/status are covered, including data (when it exists) on combining these therapies with systemic treatments.   

Intratumoral Immunotherapy Update 2019. Hamid, et al. Oncologist March 2020.

And here:

An Update on the Role of Talimogene Laherparepvec (T-VEC) in the Treatment of Melanoma: Best Practices and Future Directions.  Larocca, LeBoeuf, Silk, et al.  Am J Clin Dermatol, 2020 Dec 21.

Talimogene laherparepvec (T-VEC) is the first agent approved for cancer in the emerging class of oncolytic viral therapies. While T-VEC was approved for the treatment of advanced melanoma in 2015, clinical utilization has been hampered by rapid changes in the therapeutic landscape of melanoma related to advances in both immune checkpoint blockade and targeted therapy, cumbersome logistics involved in T-VEC administration, biosafety concerns, and a perception that T-VEC has limited impact on uninjected, visceral disease. However, with further survival follow-up from the phase III OPTiM (OncovexGM-CSF Pivotal Trial in Melanoma), along with new real-world data and consensus guidelines on safe administration of oncolytic viruses, a roadmap for when and how to use T-VEC has been emerging. In addition, preliminary data have demonstrated improved therapeutic responses to T-VEC in combination with immune checkpoint blockade in patients with melanoma without additive toxicity. This review provides an update on recent data with T-VEC alone and in combination with other agents. The emerging data provide guidance for how to better utilize T-VEC for patients with melanoma and identifies critical areas for clinical investigation to expand the role of T-VEC in combination strategies for the treatment of melanoma and perhaps other cancers.

There is this:

Oligoprogression After Checkpoint Inhibition in Metastatic Melanoma Treated With Locoregional Therapy: A Single-center Retrospective Analysis.  Comito, Leslie, Boos, et al.   J Immunother, 2020 Oct.

Checkpoint inhibitors (CPIs) have demonstrated a heterogenous spectrum of response and disease progression that may not be fully captured by conventional response criteria, such as a limited degree of progression, known as oligoprogression, which could benefit from local treatment. We retrospectively analyzed data from all patients diagnosed with metastatic melanoma, who received CPI between January 2006 and March 2018 at Royal Marsden. We enrolled 36 patients who experienced progression in a maximum of 3 metastatic sites, after achieving disease control from therapy with CPI, and were radically treated with the locoregional approach. We carried out Kaplan-Meier analysis to obtain progression free-survival post-first oligoprogression (PFS-PO1), overall survival (OS) post-first oligoprogression, and OS estimates. The median time to oligoprogression from the start of CPI was 12 months. At a median follow-up of 34 months, the median PFS-PO1 was 32 months, with 50% of patients not progressed at the time of the data cutoff. The median OS-post-first oligoprogression was not reached. At a median follow-up of 52 months (from the first cycle of CPI), the median OS was not reached, with 75% of patients alive at the time of analysis. Univariate and multivariate analyses demonstrated that baseline American Joint Committee on Cancer stage IV M1a or M1b is associated with a longer PFS-PO1 compared with stage M1c or M1d. We observed that local therapy for oligoprogression after CPI can result in durable disease control, suggesting that locoregional treatment should be considered in patients being treated with immunotherapy. However, prospective evaluation, perhaps in randomized trials, is needed. 

And this:

Durability of Complete Response to Intralesional Interleukin-2 for In-Transit Melanoma.  Khoury, Knapp, Fyfe, et al.  J Cutan Med Surg.  Feb 2021.

Background: Intralesional injection of interleukin-2 (IL-2) for in-transit melanoma (ITM) is associated with a high rate of complete response. However, there is a paucity of data on treatment durability and long-term outcomes.

Methods: Consecutive patients with ITM, treated with intralesional IL-2 therapy, at the Tom Baker Cancer Center were identified from April 2009 to August 2019. All patients received at least 4 cycles (every 2 weeks) of IL-2 (5 MIU/mL). Complete response was defined as sustained (ie, 3 months) clinical complete remission of all known in-transit disease.

Results: Sixty-five patients were treated with curative intent for in-transit disease with intralesional IL-2. Complete clinical response was identified in 44.6% (29/65). In this subset of patients, the median number of lesions per patient was 9 (range 1-40). The median total dose of IL-2 was 0.8 mL (IQR 0.4-1.5) per lesion. One patient received isolated limb infusion and 13.8% (4/29) received systemic immunotherapy as part of their initial management. At a median follow-up of 27 months (IQR 16-59), 34.5% (10/29) developed recurrent disease. Of these patients, 50.0% (5/10) presented with synchronous in-transit and distant metastases. The median time to recurrence was 10.5 months (IQR 5.8-16.3).

Conclusion: With long-term follow-up, 65.5% of complete responders have a durable response to intralesional IL-2 therapy. In this cohort of patients, local in-transit recurrence is most likely to occur within 12 months and is often associated with concomitant distant disease.

And finally, there is this from ASCO:

Talimogene laherparepvec with systemic immunotherapy in melanoma: A real-world experience.  Behera, Chen, Song, et al.  ASCO 2021.

Background: Talimogene laherparepvec (TVEC) is an FDA approved oncolytic herpes virus for intralesional therapy in unresectable metastatic melanoma. Real world data is sparse regarding the efficacy of TVEC in combination with other systemic therapies used in melanoma. We present outcomes of the largest single institution observational study of the off-label use of TVEC in combination with systemic immunotherapy.

Methods:  Patients with metastatic melanoma receiving TVEC simultaneously with ipilimumab-nivolumab (Ipi/Nivo) or single agent immunotherapy (either nivolumab or pembrolizumab) were evaluated. The demographics, clinicopathological characteristics, responses to injected lesions and remote metastatic lesions were evaluated. Clinical documentation was used to assess improvement in injected lesion size; time points for initial response and best response were identified. Review of imaging by a radiologist was evaluated to assess responses in remote metastatic lesions.

Results:  A total of 67 patients receiving TVEC from 2016 to 2020 were evaluated, of which 50 remained evaluable after excluding Merkel cell carcinoma, patients on clinical trial, TVEC monotherapy or those on BRAF-MEK inhibitors, and patients lost to follow up. In total, 29 received systemic immunotherapy simultaneously with TVEC and had been followed for at least a year, with a median follow-up time of 34 months (range, 12-56). At the time of analysis, 14 of 29 patients were alive. 6 of the 29 patients had received prior lines of therapy. Four patients received Ipi/Nivo, while 25 patients received monotherapy including 9 on nivolumab and 16 on pembrolizumab. The median number of TVEC doses received was 6 (range, 2-55) with median average TVEC dose being 3.47 ml (0.5-4 ml). Median time to initial local response was 6 weeks, whereas time to best local response was 14 weeks. Overall response rate in the injected target lesions was in 19 (66%), with complete local response (CR) in 12 (41%), partial response (PR) in 7 (24%), and progressive disease (PD) in 8 (28%). The response rate in distant non-injected lesions was 4 out of 16 (25%), 2 of which had previously progressed on prior systemic therapy. Stable disease was observed in 8 (50%) patients, and progression of disease in 4 (25%). The 1-year overall survival rate in patients receiving TVEC with systemic monotherapy was 80%. Progression free survival at 1-year in the monotherapy group was 71.6%.

Conclusions:  This is the largest single institution, real world experience to our knowledge, which assesses the efficacy of TVEC in combination with systemic immunotherapy. Our cohort suggests that TVEC is an effective treatment in combination with systemic immunotherapy, with a better overall survival observed with combination TVEC and anti-PD1 than seen with historical data from clinical trials of anti-PD-1 monotherapy.

As this mix of reports suggests, intralesional therapy can be used in several ways - as a treatment for one stubborn or new lesion in a person otherwise responding to their therapy; as an add on to pembro (Keytruda) or nivo (Opdivo) for folks with a relatively low burden of disease; or full bore combined with the ipi/nivo combo for those with more advanced disease.  The response rates are not 100%, but they are something!  And we all know, every bit helps!

Gonna shoot for getting a post up daily til done with ASCO (family, work and general life obligations withstanding)!  My fearless and determined bestie had the tough job of going through ALL the ASCO reports!!  When searching for intel on TWO cancers, that task is NOT for the faint of heart.  I have gone through his collection and broken them down into topics.  The reports will follow the pattern I have used here:  Collected, but unshared articles, followed by the selection from ASCO 2021, with my thoughts in red. 

I hope they will be of some use to a few of you.  Take good care. - c 

Intralesional Therapy....and patterns of response from the T-VEC OPTiM trial

Y'all know I'm pretty stoked about various intralesional therapies...

There is this on Rose Bengal/PV-10:  Intralesional PV-10, positive treatment for in-transit melanoma (with a link to ASCO report within)

This on CAVATAK:  ASCO 2016: CAVATAK intralesional therapy derived from the coxsackie virus

And this (containing links to many articles) on T-VEC:  ASCO 2016: T-VEC/talimogene laherparepvec with pembro

Now there is this: 

Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial.  Andtbacka, Ross, Puzanov, et al.  Ann Surg Oncol. 2016 Jun 24.   

Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy designed to induce tumor regression of injected lesions through direct lytic effects, and of uninjected lesions through induction of systemic antitumor immunity. In this study, we describe the patterns and time course of response to T-VEC from the phase III OPTiM trial of 436 patients with unresected stages IIIB-IV melanoma.

Lesion-level response analyses were performed based on the type of lesion (injected or uninjected cutaneous, subcutaneous, or nodal lesions; or visceral lesions [uninjected]), and the best percentage change from baseline of the sum of products of the longest diameters was calculated. Patients randomized to T-VEC (n = 295) who experienced a durable response (continuous partial or complete response for greater/= to 6 months) were evaluated for progression prior to response (PPR), defined as the appearance of a new lesion or greater than 25 % increase in total baseline tumor area.

T-VEC resulted in a decrease in size by greater than/= to50 % in 64 % of injected lesions (N = 2116), 34 % of uninjected non-visceral lesions (N = 981), and 15 % of visceral lesions (N = 177). Complete resolution of lesions occurred in 47 % of injected lesions, 22 % of uninjected non-visceral lesions, and 9 % of visceral lesions. Of 48 patients with durable responses, 23 (48 %) experienced PPR, including 14 who developed new lesions only. No difference in overall survival was observed, and median duration of response was not reached in patients with PPR versus those without PPR.

Responses in uninjected lesions provide validation of T-VEC-induced systemic immunotherapeutic effects against melanoma. PPR did not negatively impact the clinical effectiveness of T-VEC.

For what it's worth.... - c

Intratumoral (intralesional) therapy and a new guy in town: IL-12 Plasmid Transfection (tavo) with pembro

I've been a fan of incorporating intratumoral/intralesional therapy into melanoma care for some time.  Here's proof:  A zillion articles on intralesional therapy

Now this ~

Intratumoral Immunotherapy-Update 2019.  Hamid, Ismail, Puaznov.  Oncologist.  2020 Mar;25.

Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T-VEC), a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T-VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM-CSF (16.3% vs. 2.1%). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T-VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T-VEC in the treatment of advanced melanoma as a model for future solid tumor indications.  This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T-VEC is the only U.S. Food and Drug Administration (FDA)-approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T-VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

And this ~

Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma.  Algazi, Twitty, Tsai, et al.  Clin Cancer Res.  2020 May 6.

Tumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).

Tavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.

The combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.

The combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors.

And finally, this ~

Insights Into the Molecular Mechanisms Behind Intralesional Immunotherapies for Advanced Melanoma.  Vidovic and Giacomantonio.  Cancers (Basel) 2020 May 22. 

 The incidence of cutaneous melanoma, a highly malignant skin cancer, is increasing yearly. While surgical removal of the tumor is the mainstay of treatment for patients with locally confined disease, those with metastases face uncertainty when it comes to their treatment. As melanoma is a relatively immunogenic cancer, current guidelines suggest using immunotherapies that can rewire the host immune response to target melanoma tumor cells. Intralesional therapy, where immunomodulatory agents are injected directly into the tumor, are an emerging aspect of treatment for in-transit melanoma because of their ability to mitigate severe off-target immune-related adverse events. However, their immunomodulatory mechanisms are poorly understood. In this review, we will summarize and discuss the different intralesional therapies for metastatic melanoma with respect to their clinical outcomes and immune molecular mechanisms.

For what it's worth.  Hang tough, ratties!!! - c

CAVATAK - intralesional therapy derived from the coxsackievirus

Many intralesional therapies, medicine that is injected directly into a tumor, have been found to have some success in melanoma.  We have learned that, at times, they can not only kill the tumor into which they are injected, but "by-stander" tumors as well. First tried in 1975 with the BCG vaccine, things as disparate as IL2, Allovectin-7 (a DNA mixture), T-VEC/OncoVEX (derived from the herpes virus), L19, PV-10 (from the dye Rose Bengal), GM-CSF, and CAVATAK (derived from the coxsackievirus) have been used.  Additionally, some of these intralesionals have been tested combined with systemic immunotherapy.  The idea being that one could prime an immune response by injecting a tumor with an oncolytic virus, eliciting a T-cell influx, and follow with systemic immunotherapy.

Here's some background on the process:  Intralesional therapy for melanoma
Here is a brief review as well as reports from a study where T-VEC was combined with pembro, another with T-VEC and ipi, ipi given with IL2, as well as a report from the CALM study [don't you love their names????!!!] in which the coxsackievirus (CAVATAK) was administered singly:  From ASCO 2015: intralesional therapy for melanoma
Here's specifics on T-VEC:   Good News - local and systemic response to T-VEC
Here's the low-down on PV-10:  ASCO 2014: Rose Bengal (PV-10) with additional links
T-VEC combined with ipi: Pick your poison: Weber and Agarwala
     "When ipi is combined with T-VEC (an intralesional therapy) you get a better response rate...about 55% combined complete and partial responses....than with either drug alone."

Now....in truth....I am putting this together for my dear friend, Josh....so I am going to focus on an option he is looking at....CAVATAK with ipi.

Here is info from the CAVATAK only, CALM trial:

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

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

And this link/synopsis of Weber's "What's new in 2016" talk...discusses what's coming and recent in melanoma care as well as CALM results:  Immunology update webinar for melanoma
Within...this blurb is included:  

Intralesional Immunotherapy With Oncolytic Coxsackievirus A21 (CVA21) 
 Final response and safety data of the open-label, multicenter phaseII CALM (CAVATAK in Late-stageMelanoma) study of intratumoral CVA21 in 57 patients with unresectable stage IIIC/IV melanoma.    The study met its primary endpoint.  22 of 57 (38.6%) evaluable patients with PFS at 6 months.    Median PFS of 4.2 mos.   ORR 28.1%; median TTR 2.8 mos.  1-year survival rate 75.4%.  Median OS and median DOR not reached (16.5 mos follow-up).  Most common AEs were grade 1 fatigue, chills, fever, and injection site reactions; no grade 3/4 AEs observed.  Looks like another promising intralesional therapy.  Will soon have phase 3 study.

A link to one other report:   Viralytics reports positive final results from cavatak phase 2 melanoma trial

Here is a link to:  Intratumoral CAVATAK and ipi trial
Apparently folks will get ipi at 3mg/kg 4 times.  You have to have an injectable tumor (per their criteria) and CAVATAK will be injected 4 specific times and then every three weeks for up to one year.  The study is a Phase 1 trial, sponsored by Viralytics and was started in late 2014. You can't have taken ipi for metastatic melanoma, but you can have taken it as an adjuvant as long as you did not experience a grade 3 toxicity.  Trial is recruiting in California, Oregon and Illinois.

CAVATAK is also being studied in bladder cancer and non-small-cell lung cancer.  There is also a study combining CAVATAK with pembro for melanoma.  Here's the link:  Intratumoral cavatak and pembro trial  Here folks will get CAVATAK injections at specific times up to 19 total injections into "at least one cutaneous, subcutaneous tumor or palpable lymph node amenable to intratumoral injection" and pembro infusions every 3 weeks up to 2 years. Exclusions include:  no corticosteriods, ocular or mucosal melanoma.  No prior anti-PD1 or PDL1.  Also sponsored by Viralytics, recruiting in New Jersey.

Guess that's about all I got.  I have always been a fan of intralesional therapy...telling B that if I ever recur...and have to have some sort of surgery...I was going to beg to have Rose Bengal and lord knows what else...just splashed around in there before they sew me up.  Those who know B can imagine the big blue eye roll that comment gets me....but there you go!!!  Love you, Josh!  - c

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