Thursday, May 21, 2015

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 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

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