Provectus Provides Updated PV-10 Data on Advanced Cutaneous Melanoma

Stage III/IV immune checkpoint blockade-naïve cutaneous melanoma data.

On Wednesday, November 15, 2023, Provectus provided updated data from the Company’s ongoing Phase 1b/2 clinical trial of investigational cancer immunotherapy PV-10 (rose bengal sodium) in combination with standard of care (SOC) immune checkpoint blockade (CB) for the treatment of advanced (i.e., metastatic) cutaneous melanoma (NCT02557321).

These data play an important role in the Company’s clinical development and business strategy for, and prioritization (and validation) of, the contemplated PV-10-led combination therapy programs for pancreatic ductal adenocarcinoma metastatic to the liver, uveal melanoma (UM) metastatic to the liver (mUM), and advanced cutaneous melanoma (CM).

Twenty-five CB-naïve patients with Stage III or IV CM, comprising the main cohort (MC; 19 patients) and second expansion cohort (EC2; six patients), were treated at five sites in this Provectus multi-center study:

• Moffitt Cancer Center in Tampa, Florida, where preclinical and/or translational, multi-cancer indication research has been done (CM, breast cancer, pancreatic cancer) and is being done (head and neck squamous cell carcinoma),

• Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire,

• Oregon Health & Science University in Portland, Oregon,

• St. Luke’s University Health Network in Easton, Pennsylvania, and

• MD Anderson Cancer Center in Houston, Texas, where clinical study of PV-10 and mUM has also been done.

Study participants must have had at least one PV-10-injectable lesion and at least one measurable target lesion and been a candidate for pembrolizumab. The combination of PV-10 and pembrolizumab was administered every three weeks for up to five cycles, followed by pembrolizumab alone every three weeks for a total duration of up to 24 months. A protocol change was made for the third cohort of the study (i.e., EC2) to potentially maximize PV-10 dosing and treatment, where patients may have received PV-10 as needed (pro re nata or PRN) beyond the initial treatment course per investigator discretion. The primary endpoint (EP) of the Phase 1b portion of the trial was safety and tolerability. Objective response rate (ORR) and progression-free survival (PFS) were key secondary EPs (assessed via RECIST 1.1 after 15 weeks, and then every 12 weeks). Enrollment and treatment for the study’s three distinct patient cohorts (i.e., MC, EC1, and EC2) are complete. Only survival follow-up continues.

Clinical sites in Australia were interested in participating in the study; however, the country’s Pharmaceutical Benefits Scheme (PBS) ostensibly precluded CB reimbursement as part of CB-naïve melanoma combination therapy, based on Provectus’s initial, historical interpretation of Australian-approved monotherapy CB prescribing information (our view has since changed based on feedback from a commercial-stage pharmaceutical company). In addition, under the country’s “one-and-done” policy for CB, PBS ostensibly reimbursed or reimburses patients for one course of CB treatment, which ostensibly precluded CB-refractory patients from receiving PV-10 + CB (the first expansion cohort [EC1]) (our view may also be informed here too).

In the advanced CM data update provided the Company:

• Six Stage IIIB-IIIC (24%), eight Stage IV M1a (32%), seven M1b (28%), and four M1c (16%) CB-naïve patients, all per the American Joint Committee on Cancer (AJCC) melanoma staging system, were treated,

• Safety. Treatment-emergent adverse events were consistent with the established patterns of both study drugs, with no evidence of overlap,

• Response. For all patients, overall patient ORR was 72%: 20% complete response (CR) and 52% partial response (PR). For Stage III patients, ORR was 83%: 50% CR and 33% PR,

• Durability of response. For all patients, median PFS (mPFS) was 12.5 months. For Stage III patients, mPFS was not reached, and

• Survival. For all patients, median overall survival (mOS) was 37.6 months (3.1 years), and median disease-specific survival (mDSS) was 64.4 months (5.4 years). For Stage III patients, mOS and mDSS were estimated to be 36.3 months (3.0 years) and 42.5 months (3.5 years), respectively; median survival was estimated, and could increase, because the last treated Stage III patient was an ongoing complete responder at 30.1 months (2.5 years).

Melanoma treatment landscape.

The treatment landscape for melanoma — from various perspectives (e.g., a patient, a biotechnology company, first-line or second-line treatment, CB-naïve or CB-refractory, early-stage or late-stage disease) — is essentially/mostly monotherapy CB or combination therapy CB:

• Ipilimumab (CTLA-4; Yervoy^®),

• Pembrolizumab (PD-1; Keytruda^®),

• Nivolumab (PD-1; Opdivo^®),

• Ipilimumab + nivolumab (CTLA-4 + PD-1), and

• Nivolumab + relatlimab (PD-1 + LAG-3; Opdualag^®).

Provectus has strong, diverse, clinical experience combining PV-10 and CB:

• PV-10 + PD-1 (pembrolizumab, nivolumab): CM¹, metastatic uveal melanoma², mucosal melanoma of the vagina³, and breast cancer⁴,

• PV-10 + PD-L1 (avelumab/Bavencio^®): Merkel cell carcinoma⁵, and

• PV-10 + CTLA-4 + PD-1 (ipilimumab + nivolumab): metastatic uveal melanoma⁶.

Timeline.

Provectus’s CM & CB program (PV-10 + pembrolizumab) started in early-2015, when the program began enrollment, to late-2023, as clinical work wrapped up:

• Cohort #1: The MC of 19 patients who had CB-naïve Stage IV disease,

• Cohort #2: A first expansion cohort (EC1) of 22 patients who had CB-refractory Stage IV disease, and

• Cohort #3: An EC2 of six patients (two of whom were originally enrolled as part of the main cohort) who had CB-naïve Stage III disease.

For both the MC and EC1, customary “round” numbers were used for enrollment targets (e.g., 18 to 24 patients per cohort). Based on (i) our assessment of the MC and EC1 data, (ii) subsequently making the abovementioned clinical trial protocol changes, and (iii) our assessment of the EC2 data (e.g., overall patient response, durability of response, survival) that were strong and potentially predictive of our PV-10 treatment thesis (i.e., a little PV-10 goes a long way, but enough PV-10 might potentially cure you), further EC2 enrollment was stopped.

Like the mUM program (the subject of November 18, 2023 Substack titled “Provectus Provides Updated PV-10 Data on Metastatic Uveal Melanoma”), we also worked through several issues as the CM program coalesced over time, among them: PV-10 dosing regimen, treatment response to PV-10-led combination therapy, durability of such responses, survival, and mechanism of immune action. See May 15, 2023 Substack post titled “Cancer immunotherapy PV-10’s evolution into a cancer immunotherapy” and Study #4. As we noted the Substack post, the first two cohorts of the CM study principally transgressed Principal A of optimized PV-10 pharmacokinetics by only providing an initial number of cycles of PV-10 and not treating as much existing and/or new disease as possible (i.e. inject/reinject baseline/new lesions – “touch and treat”) prior to first tumor response measurement.

Like PV-10’s cancers of the liver program (e.g., hepatocellular carcinoma, colorectal cancer, neuroendocrine tumors, mUM, etc.), PV-10’s CM program has had the benefit of extensive monotherapy experience (e.g., Phase 1 to 3 trials), where the data are clearly indicative of the drug activity of monotherapy PV-10.

Competitive Landscape.

Provectus’s PV-10 + pembrolizumab data for CB-naïve Stage IV CM are competitive with CB monotherapy and combination therapy data, comparing PV-10’s single-arm trial (SAT) data to CB randomized controlled trial (RCT) data:

• Ipilimumab: 26% 5-year OS rate, 18% ORR, 2.9 months mPFS, 19.9 months mOS (Larkin et al. 2019, minimum 60 months follow-up)

• Pembrolizumab: (a) 41% 5-year OS rate, 52% ORR, 16.9 months mPFS, 38.6 months mOS (Hamid et al. 2019, median 55 months follow-up); (b) 38.7% 5-year OS rate, 8.4 months mPFS, 32.7 months mOS (Robert et al. 2019, median 57.7 months follow-up),

• Nivolumab: 44% 5-year OS rate, 45% ORR, 6.9 months mPFS, 36.9 months mOS (Larkin et al. 2019),

• Ipilimumab + nivolumab: 52% 5-year OS rate, 58% ORR, 11.5 months mPFS, 60.0 months mOS (Larkin et al. 2019), and

• Nivolumab + relatlimab: 51.5% 4-year OS rate (vs. 42.5% nivo), 43.7% ORR (33.7%), 10.2 months mPFS (4.6 months), mOS not reached (33.2 months) (Tawbi et al. 2023, median 25.3 months follow-up).

Past PV-10 CM Data.

We last updated data for the CM study’s three cohorts as noted below:

• CB-naïve Stage IV: ESMO Virtual Congress 2020 (two Stage III patients out of 19),

• CB-refractory Stage IV: SMR 2021 (one Stage III patient out of 22), and

• CB-naïve Stage III: Melanoma Bridge 2022.

The recent data readout provided updated survival of patients in the CB-naïve cohorts.

Forward-Looking Statements

The information in Provectus’ Substack post may include “forward-looking statements,” within the meaning of U.S. securities legislation, relating to the business of Provectus and its affiliates, which are based on the opinions and estimates of Company management and are subject to a variety of risks and uncertainties and other factors that could cause actual events or results to differ materially from those projected in the forward-looking statements. Forward-looking statements are often, but not always, identified by the use of words such as “seek,” “anticipate,” “budget,” “plan,” “continue,” “estimate,” “expect,” “forecast,” “may,” “will,” “project,” “predict,” “potential,” “targeting,” “intend,” “could,” “might,” “should,” “believe,” and similar words suggesting future outcomes or statements regarding an outlook.

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated or that such agents as products will achieve any particular revenue levels.

Due to the risks, uncertainties, and assumptions inherent in forward-looking statements, readers should not place undue reliance on these forward-looking statements. The forward-looking statements contained in Provectus’ Substack are made as of the date hereof or as of the date specifically specified herein, and Provectus undertakes no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except in accordance with applicable securities laws. The forward-looking statements are expressly qualified by this cautionary statement.

Risks, uncertainties, and assumptions include those discussed in the Company’s filings with the Securities and Exchange Commission (SEC), including those described in Item 1A of:

• the Company’s Annual Report on Form 10-K for the year ended December 31, 2022, and

• Provectus’ Quarterly Report on Form 10-Q for the period ended September 30, 2023.

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