March 18, 2016

Things May Get Worse Before They Get Better, Unless They Get Better Right Away

On the blog's Current News page I wrote about the tumors of patients who received and responded to treatment with Amgen's talimogene laherparepvec (T-Vec, or trade name Imylgic) that increased in size (i.e., following injection of IL drug T-Vec, the tumors appeared to progress) before they decreased in size or shrunk. See Progression Prior to Response (PPR) (March 17, 2016) and #3 under To Dos (March 16, 2016).

This transient tumor behavior of getting bigger before getting smaller (and hopefully going away) is referred to as pseudo-progression. This phenomenon was observed in patients suffering from glioblastoma multiforme (brain cancer) who received chemotherapy (e.g., temozolomide).

Some patients receiving immunotherapies like anti-CTLA-4 drug ipilimumab (Yervoy) as well as anti-PD-L1 drugs pembrolizumab (Keytruda) and nivolumab (Opdivo) also experienced pseudo-progression in clinical trials. Such transient behavior is with a delayed immune response. See, for example, Pseudoprogression and Immune-Related Response in Solid Tumors, Chiou et al., J Clin Oncol. 2015 Nov 1;33(31):3541-3.

BioVex, which designed T-Vec's pivotal Phase 3 trial, when it was called OncoVEX (GM-CSF), constructed it to facilitate some amount of time to elapse before assessment tumor response -- so as to not mischaracterize pseudo-progression as progression. Some clinical trials may employ so-called immune-related response criteria (irRC) to address pseudo-progression.

Pseudo-progression can occur by 12 weeks of imaging and maybe later.

Provectus' pivotal Phase 3 trial uses RECIST v. 1.1, which as I previously noted defines disease progression as an increase in overall lesion size of >20%. I also observed that half of the responding patients in T-Vec's Phase 3 trial experienced an increase in overall lesion size of ≥25% and/or developed at least one new lesion prior to ultimately achieving a response. T-Vec's trial used a modified WHO tumor assessment method. Provectus' CTO Dr. Eric Wachter, PhD's Phase 3 trial design seems to me to be a pretty down-the-middle-of-the-fairway approach, and a thoughtfully and carefully constructed one at that.

So, my comments about T-Vec, modified WHO vs. RECIST 1.1, pseudo-progression, event generation, etc. need to be taken into context, or better communicated by me.

Tumors injected with PV-10 do have a reaction: There can be some local inflammatory response, and occasionally there is ablation beyond the apparent tumor margin, but in general there's no pseudo-progression over the timeframe experienced by T-Vec, ipi, pembro, nivo, etc.

See, for example, Locoregional Disease Control in Metastatic Melanoma: Exploratory Analyses From Phase 2 Testing of Intralesional Rose Bengal, European Cancer Congress 2013, Abstract No. 3.755, Sep 2013.

One might remember Moffitt Cancer Center's Dr. Shari Pilon-Thomas' comments regarding the center's mechanism of action work: "Ironically, the original aim of the trial to assess tumor-infiltrating lymphocytes was thwarted when biopsies of patient tumors collected just 7-14 days after PV-10 injection no longer contained viable tumor tissue." {my bolded and underlined emphasis} (source: Provectus's April 2014 press release Induction of Systemic Immunity Following Treatment of Tumors with PV-10 Reported by Moffitt Cancer Center Researchers at American Association for Cancer Research Annual Meeting)

Takeaway: PV-10's tumor ablation effectiveness often is not only complete, but it is quickly complete. In the pivotal Phase 3 trial, it might occur before the first clinical assessment, and certainly/hopefully before the assessment to ascertain progression-free survival.

A cycle below is about one month or 4 weeks. A follow-up below is about 3 months or 12 weeks.
Click to enlarge.

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