Debating Systemic Intralesional Therapies (April 16, 2014)
See Moffitt & Dr. Jeff Weber (April 14, 2014) below. Weber's debate with Ross centered on the benefit or lack thereof of intralesional (“IL”) therapies for heavily diseased patients (heavy tumor burden) with visceral metastases.
(from connecting the dots today)
According to HemOnc Today, "Weber notes that in an age of increasingly effective systemic therapies for stage IV melanoma, it would be difficult to rationalize the use of intralesional therapy alone in more than select subgroups of patients with dermal metastases only. Furthermore, Weber asserts that without significant benefit in PFS and OS, local regression is an insufficient substitute to validate continued interest in current intralesional therapies as a monotherapy."
Viewing Weber's video short I linked to above, one hears (paraphrasing, or noting):
•He has 25 years of experience with IL therapies. He observed that while they have some local benefit or affect, IL therapies are extremely unlikely to have significant systemic benefit.
•The issue at stake in the debate was whether there is a significant systemic role; that is, whether intralesional therapies impact systemic disease. The issue, as it relates to framing the debate, was that patients who die of melanoma die of distant metastatic disease; they do not die from locoregional, cutaneous, dermal or soft tissue disease.
•Amgen's T-Vec trial, while well done, showed modest impact on systemic metastases. He noted T-Vec's distant response of non-injected visceral metastases was 16%, versus 76% for BRAF/MEK drug combinations, a modest 10-15% for Ipilimumab but that has shown 20% 5-year survival for predominantly Stage IV M1c disease, and PD-1 and PD-L1 antibodies that have shown 30-40% response rates and 16.8-month survival for predominantly M1c disease.
•He is hard pressed to see a systemic role for IL therapies like T-Vec in patients with significant disease burden and visceral M1c disease. Stages IIIB-C and IV M1a patients could be treated with IL therapy. To expect, however, significant clinical and biologic systemic benefit (affect) with any IL therapy as we now know them is very low. {Underlined emphasis is mine}
Weber’s HemOnc conference presentation is available at this link. Several things about his comments and presentation (and as they relate to Provectus and PV-10) are interesting. First, his focus in the debate as it related to the use and utility of IL therapies was for patients with significant disease burden and visceral M1c disease, a small fraction of the total melanoma market.
Second, without significant benefit in survival-based endpoints like progression free survival (“PFS”) and overall survival (“OS”), objective response or OR (e.g., complete response, partial response) has not translated for IL therapies into success for Stage IV M1c patients, and more broadly Stage IV in most cases. Systemic disease requires the use of survival-based endpoints. OS is a metastatic melanoma label.
You may recall Dr. Andtbacka's comparison table of IL therapies and their Phase 2 results for metastatic melanoma. Although Vical’s Allovectin-7 and Amgen's T-Vec achieved notable OR results in their Phase 2 trials, comparably successful OS results were not achieved in their Phase 3 trials.
Click on the figure to enlarge it.
Allovectin-7's Phase 2 trial comprised 53% Stage 3 patients and 47% Stage 4, while T-Vec's Phase 2 trial comprised 20% Stage 3 patients and 80% Stage 4. PV-10's Phase 2 trial comprised 77.5% Stage 3 patients and 22.5% Stage 4. Although Provectus' Phase 2 trial included some patients with systemic and visceral disease, patient selection was focused on those where PV-10 might achieve loco-regional disease control and thus forestall or prevent metastatic disease.
T-Vec's Phase 3 trial patient staging comprised 30% Stage IIIB-C and 70% Stage IV (27% M1a, 21% M1b and 22% M1c 22%). Provectus' contemplated pivotal Phase 3 trial (under special protocol assessment) would have been comprised of 100% Stage IIIB-C patients. T-Vec's trial used survival-based endpoints of durable response rate (primary) and OS (survival). Provectus' Phase 3 trial design would have used PFS.
T-Vec stumbled through a trial designed to prove, by virtue of survival-based endpoints, its value for treating systemic disease. PV-10 is being evaluated by the FDA using tumor-based endpoints (i.e., a primary endpoint of complete response) for its potential to achieve loco-regional disease control, and forestall or prevent the onset of systemic disease.
Systemic disease v. loco-regional disease. Survival-based endpoints vs. tumor-based endpoints. OS/PFS vs. CR.
Third, I was struck by Weber's “…as we now know them [IL therapies]…” comment. The phrase seems to me very interesting and a tad intriguing in light of Moffitt’s historical, presented and published, yet to be presented and published, and rumored pre-clinical and clinical work on PV-10. Weber's HemOnc presentation (see slide #4 below, for example) omitted mention and reference to PV-10.
