Friday, May 27, 2016

ASCO 2016 - immunotherapy after HD IL-2 and vice versa - HD IL-2 after anti-PD1

Update on the overall survival of patients with metastatic melanoma treated with immune checkpoint blockade following initial treatment with HD IL-2.  ASCO 2016.  # e21039.  J Clin Oncol 34, 2016.  Wong, Morse, McDermott, et al. 

Background: High-dose interleukin-2 (HD IL-2) and immune checkpoint inhibitors can provide survival benefit in patients with metastatic melanoma (mM). The clinical impact of using these therapies in sequence remains unknown. Herein, we report on the outcomes of sequencing ipilimumab and/or anti-PD-1/PD-L1 therapy after treatment with HD IL-2 using a national IL-2 patient registry, PROCLAIMSM . Methods: Patients were prospectively enrolled into the registry as of 2011 and must have received at least one dose of HD IL-2 for this analysis. Those that received immune checkpoint inhibitors prior to HD IL-2 were excluded. Statistics and survival analysis were performed on datasets as of December 2, 2015. Results: The mOS for all mm patients (n = 273) was 19.4 months, with a median follow-up of 23.1 months. Three groups were further analyzed according to treatment after HD IL-2; no immune checkpoint blockade following HD IL-2 (no ICB, n = 137), HD IL-2 followed by ipilimumab alone (IL-2 then IPI, n = 82), and HD IL-2 followed by anti-PD-1/PD-L1 inhibitors with or without ipilimumab (IL-2 then aPD-1±IPI, n = 54). This latter group, IL-2 then aPD-1±IPI, could have received ipilimumab before or after anti-PD-1/PD-L1. Patients with no ICB, IL-2 then IPI, and IL-2 then aPD-1±IPI achieved a mOS of 14.1, 15.8, and 28.2 months, respectively. The estimated 12-month survival rates were 56%, 64%, and 96%, respectively. No HD IL-2 treatment-related deaths were reported. Conclusions: There was no difference in mOS between patients treated with ipilimumab post HD IL-2 compared to patients with no ICB [no immunotherapy] following HD IL-2. Patients treated with anti-PD-1/PDL-1±IPI showed increased mOS compared to those treated with HD IL-2 alone. These data further support the concept of investigating IL-2 therapy in combination or sequence with newly developed immune checkpoint inhibitors. Clinical trial information: NCT01415167

12 month survival rates:
56% - no immunotherapy after HD IL2
64% - ipi after HD IL2
96% - antiPD1 after HD IL2 with or without ipi

A Prospective Analysis of High-Dose Interleukin-2 (HD IL-2) following PD-1 inhibitor therapy in patients with metastatic melanoma and renal cell carcinoma.  ASCO 2016.  # e21006.  J Clin Oncol 34, 2016.  Buckbinder, Dutcher, Perritt, et al.

Background: PD-1/PD-L1 inhibitors (aPD-1) have demonstrated efficacy in the treatment of metastatic melanoma (MM) and advanced renal cell carcinoma (RCC). HD IL-2 can produce durable responses in a subset of patients and remains a treatment option. As aPD-1 therapy becomes the backbone of mm and RCC treatment it becomes increasingly important to understand whether HD IL-2 is safe and effective following immune checkpoint blockade (ICB). Methods: PROCLAIMSM  is an IL-2 observational registry with more than 40 participating sites consisting of a retrospective (n = 370, locked) and prospective cohort (n greater than 942, on-going). We queried the prospective cohort to identify pts treated with HD IL-2 after aPD-1 and report their safety and efficacy outcomes, compared to pts who had not received any ICB prior to HD IL-2. Results: Within the database, there are currently 16 patients who received aPD-1 prior to HD IL-2 therapy, 12 patients (3 RCC and 9 MM) had sufficient data as of 12/17/2015 to analyze outcome. Of these 12 patients, seven with mm also received ipilimumab and 3 with RCC also received anti-VEGF therapy prior to treatment with HD IL-2. The most common and reversible toxicities reported as the reason(s) to stop dosing for Cycle 1 in the patients who had previously been treated with aPD-1 were hypotension, diarrhea, vomiting, hypoxia, renal failure and arrhythmia. These toxicities were similar to those observed among the 681 HD IL-2 patients without prior ICB. There were no IL-2 related deaths noted in the cohort receiving prior aPD-1. The one year overall survival from HD IL-2 was 76% in patients who previously received aPD-1 versus 74% in patients who had not previously been treated with ICB. The ORR was 8.3% in patients with prior aPD-1 vs. 15% in those without prior ICB. Conclusions: Data from the PROCLAIM database suggests that HD IL-2 remains a treatment option for pts who have had progressive disease after prior PD-1 inhibition. Continued analysis of patients treated with HD IL-2 will help guide the optimal sequence of these immunotherapies.

Interesting that OS was a bit higher in those who had received anti-PD1 THEN IL2, but response rate was better when IL2 was taken BEFORE any immunotherapy.  It seems there is still much to learn.   - c

Thursday, May 26, 2016

ASCO 2016: New studies! Rose Bengal and Pembro for Stage IV y'all!!! Enrolling! For Stage IIIb/c: PV-10 vs T-VEC.

I've been singing about Rose Bengal for some time!  Recently this study showed a bit about how it works...and there are links to previous posts  Now there is this:

Intralesional rose bengal for treatment of melanoma.  ASCO 2016. #9600.  J Clin Oncol 2016.  Agarwala, Andtbacka, Rice, et al.

Background: Intralesional rose bengal (PV-10) is an investigational small molecule ablative immunotherapy that can elicit primary ablation of injected tumors and secondary T-cell activation. Phase 2 testing in Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. PV-10 is currently undergoing phase 3 testing as a single agent in patients with locally advanced cutaneous melanoma and phase 1b testing in combination with immune checkpoint inhibition for more advanced disease. Methods: Study PV-10-MM-31 is an international multicenter, open-label, randomized controlled trial of PV-10 versus investigator’s choice of chemotherapy (dacarbazine or temozolomide) or oncolytic viral therapy (talimogene laherparepvec). A total of 225 subjects with locally advanced cutaneous melanoma (Stage IIIB or Stage IIIC recurrent, satellite or in-transit melanoma) randomized 2:1 will be assessed for progression free survival (PFS) by RECIST 1.1 (using blinded Independent Review Committee assessment of study photography and radiology data). Comprehensive disease assessments, including review of photography and radiology data, are performed at 12 week intervals; clinical assessments of progression status are performed at 28-day intervals. Study PV-10-MM-1201 is an international multicenter, open-label, sequential phase study of PV-10 in combination with pembrolizumab. Stage IV metastatic melanoma patients with at least one injectable cutaneous or subcutaneous lesion who are candidates for pembrolizumab are eligible. In the current phase 1b portion of the study, up to 24 subjects will receive the combination of PV-10 and pembrolizumab (PV-10 + standard of care). In phase 2 an estimated 120 participants will be randomized 1:1 to receive either PV-10 and pembrolizumab or pembrolizumab alone. The primary endpoint for phase 1b is safety and tolerability with PFS a key secondary endpoint; PFS is the primary endpoint for phase 2. Clinical trial information: NCT02288897

Really love that there is a head to head look at PV-10 vs T-VEC.  The fact that they had to throw chemo in there pisses me off...but...  Love the idea of anti-PD1 with intralesionals.  Many researchers have been looking at this as the best way to use intralesional therapy.  

And then there's this:  Rose Bengal and Radiation....Overall response rate of 87%!

A phase 2 study of intralesional PV-10 followed by radiotherapy for localized in transit or recurrent metastatic melanoma.  ASCO 2016. # e21072.  J Clin Oncol 34, 2016.  Foote, Burmeister, Thomas, et al.  

Background: Intralesional rose bengal (IL PV-10) can elicit ablation of injected tumors and a T-cell mediated abscopal effect in untreated lesions. Phase 2 testing in patients with Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. Three patients who progressed received external beam radiotherapy (XRT) to their recurrent lesions with an impressive response without an increased radiation reaction. Methods: An open-label, single-arm phase 2 study was performed to assess efficacy and safety of IL PV-10 followed by XRT. Eligibility included recurrent localized dermal, subcutaneous, in-transit or metastatic malignant melanoma (stage IIIb / IIIc) suitable for intralesional therapy and XRT. Patients received a single course of PV-10 into lesions treatable within a localized radiotherapy field. If CR was not achieved patients received 30 Gy (6 fractions of 5 Gy twice weekly over 3 weeks) 3D conformal radiotherapy (photons or electrons) commencing 6-10 weeks after PV-10. Outcome assessments included ORR and clinical benefit (CR+PR+SD) of in-field target lesions by RECIST criteria, toxicity using CTCAE V3.0, and progression free survival (PFS). Results: There were 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. Treatments were well tolerated with no treatment associated grade 4 or 5 adverse events. Conclusions: The combination of IL PV-10 and radiotherapy resulted in lesion specific, normal tissue sparing, ablation of melanoma tumors with minimal local or systemic adverse effects. The study results justify expanded evaluation in a randomized trial.

Wow!!! Good luck, ratties! - c

Wednesday, May 25, 2016

ASCO 2016: CAVATAK (intralesional treatment derived from the Coxsackievirus) Factors that improve response!

I recently posted this:  CAVATAK Intralesional therapy for melanoma

Here's what was posted at ASCO regarding factors that improved response....

Dynamics of tumor response in advanced melanoma patients treated with Coxsackievirus A21.  ASCO 2016. #9553.  J Clin Oncol 2016.  Andtbacka, Curti, Kaufman, et al.

Background: CAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of Coxsackievirus A21 (CVA21). Intratumoral (IT) injection of CVA21 induces lytic tumor cell infection, up-regulation of immune checkpoint molecules and increased immune-cell infiltration. The Phase II CALM study investigated the efficacy and safety of IT CVA21 in 57 pts with advanced melanoma resulting in a confirmed ORR of 28.1% and DRR of 21.1%. The CALM extension study (13 pts) investigated CVA21 induced changes in immune cell infiltrates within the tumor-microenvironment (TME). We describe factors regarding the nature of clinical responses in 70 pts with stage IIIC-IV melanoma given IT CVA21. Methods: The association of prior lines of therapy, tumor pseudo-progression, baseline tumor burden (BTB) and levels of immune cell infiltrates in the TME were examined with regard to clinical response. Results: 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. Three pts (18.8%) exhibited pseudo-progression (irRECIST criteria) prior to response. BTB of the 57 pts in the CALM study was 3.9 cm. A BTB less than median was associated with: superior ORR (39.3 vs 17.2 %), superior DRR (35.7 vs 6.9 %), and greater OS. In the CALM extension study, CVA21 tx induced increases in immune cell infiltrates within the TME. In patients with responses, increases in CD8+ T-cells and PD-L1+ expression were observed in injected lesions. Reconstitution of immune cell infiltrates was observed in a number of CVA21 treated lesions from pts failing prior tx with immune-checkpoint blockade. Conclusions: IT administration of CVA21 can notably influence the dynamics of the TME and generate systemic anti-tumor immune responses as evidenced by increases in immune cell infiltrates and widespread non-injected lesion responses. Clinical trial information: NCT01227551

These are small numbers, but...CAVATAK certainly changed the tumor-microenvironment, worked in treated and UN-treated lesions, previous treatment with ipi or T-VEC may make it work better, and as would be expected, folks with a lower tumor burden did better.  Pseudoprogression was also noted at times.

It seems reasonable to assume that combining CAVATAK with a systemic therapy (as noted in the prior post) should improve responses! -c

Tuesday, May 24, 2016

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 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.....  "'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."'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 

Monday, May 23, 2016

ASCO 2016 - Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!

Now this is just little 'ol me talking...but if patients who had to stop the combo early due to side an OS at 18 months that is the same as those who who continued says to me that we are giving the meds too long!!!!  Of course we will have to see if that holds over time, but way to go, ratties!!! - c

Overall survival in patients with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to toxicity in a phase II trial (CheckMate 069).  ASCO 2016. #9518.  J Clin Oncol 2016.  Hodi, Postow, Chesney, Pavlick, Robert, Agarwala, Wolchok, et al.

Background: Results from CheckMate 069 demonstrated a significant improvement in objective response rate (ORR) and progression-free survival (PFS) with NIVO+IPI vs IPI alone in treatment-naïve patients  with BRAF wild-type MEL. We evaluated overall survival (OS) in pts who discontinued treatment due to toxicity in this study. Methods: Pts (N = 142) were randomized 2:1 to receive NIVO 1 mg/kg plus IPI 3 mg/kg or IPI 3 mg/kg plus placebo every 3 weeks x 4 doses, followed by NIVO 3 mg/kg or placebo, respectively, every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was ORR in pts with BRAF wild-type tumors. Secondary and exploratory endpoints included PFS and OS. A post-hoc analysis was performed to evaluate OS in pts who discontinued treatment due to toxicity. Results: At a follow-up of greater than or = to,18 months, median OS in pts who discontinued treatment was not reached with NIVO+IPI and was 11.2 months for IPI alone. Similar 18-month OS rates were observed in pts who discontinued NIVO+IPI due to toxicity and in the overall treatment group. Among pts who discontinued NIVO+IPI, ORR was 68% (27% achieved a complete response). Median duration of response was not reached and 21 of 30 pts (70%) remain in response. Grade 3/4 treatment-related adverse events (AEs) occurred in 55% of pts in the NIVO+IPI group vs 22% with IPI, and led to discontinuation in 30% and 9% of pts, respectively. In pts who discontinued NIVO+IPI due to toxicity, resolution rates of treatment-related select AEs ranged from 89% to 100% (40% for endocrine AEs). Efficacy updates, including 2-year OS rates, will be presented for these pts. Conclusions: These data suggest that pts who discontinue NIVO+IPI treatment due to drug toxicity derive an OS benefit similar to that observed in the overall population. Clinical trial information: NCT01927419

All randomized pts who discontinued due to toxicity

All randomized
BRAF wild-type pts

(n = 44)
(n = 10)
(N = 72)
(N = 37)
Median OS, months   

18-month OS rate, %