"The high rate of symptom control in refractory patients, manifest in CR of injected lesions after minimal intervention, was the basis for a breakthrough therapy designation application to the US FDA based on the 28 patient “all treated” subgroup..."
"...and implications of the Agency’s ruling on this application will be presented."These implications appear to be the enablement of the Phase 3's study design through, per the poster:
- "Facilitating dialog with regulatory authorities on patient population and endpoints
- Suggesting a substantial PFS advantage for PV-10 over historical data on comparator
- Enabling optimization of PV-10 dose schedule"
Changes in the Phase 3 trial design in the ESMO poster compared to the ASCO one include:
- An estimated sample size of 219 (compared to 210),
- Four week treatment cycles (PV-10 or DTIC/TMZ) during initial 12 week treatment phase (compared to three week), and
- [From a poster perspective] the reordering of secondary endpoints placing patient reported outcomes ("PROs") above overall survival ["OS"] (compared to OS above PROs)
The poster also teased the upcoming Moffitt murine model work to be presented on a poster at SITC in November (sub-titled in the ESMO poster's conclusion PV-10 with Immune Checkpoint Blockade for Widely Metastatic Disease):
- "Emerging immunology data supports T-cell mediated tumor-specific response secondary to PV-10 ablation
- Data to be presented in November on IL PV-10 in combination with immune checkpoint blockade in melanoma models may indicate clinical studies are warranted
- Design of a Phase 1b/2 combination study is underway"
Contrast the ESMO 2014 poster conclusion below...
...with the ASCO 2014 poster "Path Forward" section below.
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PR quote #1: Commenting on the poster, Dr. Agarwala said, "Although the primary ablative effect of PV-10 can lead to rapid regression of injected lesions, durability of response may signal the effects of an immunologic process secondary to ablation. In addition to offering the potential to relieve symptoms of cutaneous melanoma, a robust, tumor-specific immunologic response could have the potential of changing the course of the disease." {Underlined emphasis is mine.}
Dr. Agarwala, from St. Luke's University Hospital/St. Luke's University Health Network of Bethlehem, Pennsylvania, addresses two points. First, he notes the durability or length of PV-10's response on lesions following injection (noting the last allowed injection was at week 16). Durability and durable benefit should materially contribute to long-term survival and benefit. The associated poster portion is below.
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Second, Agarwala addresses both components of PV-10's two-step mechanism of action, (a) rapid ablation and (b) immunomodulation. The associated poster portion is below.
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In each case, his comments contextualize cutaneous melanoma -- the most common type of melanoma -- and PV-10's role in defeating or containing it. Defeat would come through complete response. The FDA, however, wanted, at the time of breakthrough therapy designation ["BTD"] application, and wants, via the upcoming pivotal Phase 3 trial, the association (correlation) between complete response and symptom control more fully elucidated. Containment comes through demonstrating that if you truly effectively treat disease in Stage III (or, of course, earlier or much earlier), it forestalls or prevents it from progressing to Stage IV. See blog post Treating Cancer, and news item How much is enough, and when? (September 16, 2014).
Quote #2: Eric Wachter, PhD and Chief Technology Officer of Provectus, said, "We are very pleased to share the patient-level PFS data at ESMO that defined our design parameters for the upcoming phase 3 trial. These study results demonstrate the potential of an intralesional approach to delay progression while alleviating symptoms of locally advanced melanoma." {Underlined emphasis is mine.}
The underlined sentence above asserts the clinical value proposition of PV-10 as appropriate for the treatment of local disease, the vast majority of the melanoma market and comprised of the silent masses for which surgery, chemotherapy, etc. are their only options.
Quote #3: Wachter continued, "We are looking forward to initiation of the phase 3 trial and have assembled an experienced multi-disciplinary team to help us execute this important study. For example, we are thrilled to collaborate with ERT, Inc., experts in quantifying patient reported outcomes for pivotal oncology trials, and expect this collaboration to help place Provectus at the forefront in the study of cutaneous symptoms of locally advanced melanoma." {Underlined emphasis is mine.}
It seems to me the secondary endpoint of PROs is quite important for this patient population indicating cutaneous symptoms of locally advanced melanoma, and is addressed by Agarwala and Eric. Interestingly, and I suppose not the least bit ironically, there does not appear to be medical literature that tabulates and documents that if you stop melanoma at Stage III (when, generally speaking, if you effectively and comprehensively treat the patient you can save him or her) it won't progress to Stage IV. Potential innovational cancer drug treatment progress like PV-10 still seems to boil down to having to show that effective local treatment (where the treatment does not have to be systemic) can be a good thing. It would seem only Provectus is doing this approach of studying cutaneous symptoms in relation to ablation, and ultimately having the goal of showing when disease (melanoma) is ablated in Stage III it is forestalled from getting to Stage IV.
Quote #4: Wachter concluded, "[i] The data presented at ESMO were fundamental in allowing us be in a position to commence pivotal testing of PV-10 in locally advanced melanoma patients. [ii] Furthermore, understanding the bystander effect is critical to rational combination of PV-10 with systemic drugs in patients with significant disease inaccessible to intralesional injection, and [iii] we look forward to seeing additional data on this important topic in coming months." {Parenthetical numbering is mine.}
i. I presume this sentence refers to implications in the abstract where Provectus wrote (see underlined emphasis below): "The high rate of symptom control in refractory patients, manifest in CR of injected lesions after minimal intervention, was the basis for a breakthrough therapy designation application to the US FDA based on the 28 patient “all treated” subgroup, and implications of the Agency’s ruling on this application will be presented." The FDA's BTD denial letter referenced a determination "...based on the paucity of data on endpoints indicative of clinical benefit (e.g., pain, infection, significant bleeding)..." According to the portion of the ESMO poster below (this portion also was part of the company's ASCO 2014 poster), only 13 patients in the All Melanoma Followed (N=54) provided trackable data related to symptomatic status. How many of the subset of this group, All Lesions Treated, the basis for the BTD application, provided trackable symptomatic information? In hindsight, the answer was not enough. Eric understood it to be a "measured risk" (a phrase from the company's May 23rd conference call) to submit for BTD without enough symptomatic data; however, as he said on the same call, "...our logic seemed clearer that if we were making the patients' tumors disappear in 50 percent of the patients that was a very large effect size, and that was tantamount to making any symptoms that they might have been suffering from the tumor burden disappear."
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ii. The bystander effect represents PV-10's immunologic activity, locally in terms of (a) locoregional blistering, which Provectus believed "...may be indicative of nascent local immunologic response" (ECCO 2013) and, I believe, (b) pathologic complete response (ASCO 2014), where presumably even occult cells are destroyed, and systemically. Understanding this immunologic activity, in terms of the steps of the cancer immunity cycle that PV-10 promotes, and seeing more data will be key to the interest of Big Pharma wishing to combine their immune checkpoint inhibitors with PV-10. As the global development team leader of an immune checkpoint inhibitor said to me: "I'm not familiar with hard data on PV-10 having strong immunologic properties...However, if [it] does generate significant anti-cancer immune responses that are inhibited by [their immune checkpoint inhibitor], then such a combo could make sense."
iii. Teasing Moffitt Cancer Center's presentation at SITC 2014, and possible related data publication(s) prior to this conference.
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