The article below is a cut and paste copy of the linked article. I found it striking .... and I mean that in a positive way ..... that PV-10 was included right up front with other investigational MM drugs. Clearly, PV-10 is not the only drug being developed to combat melanoma but, as I see it, PV-10's efficacy and safety continue to outpace the competition and recognition of it is building.
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Reports from the 50th American Society of Clinical Oncology
(ASCO) Annual Meeting
http://www.pvct.com/news/OncologyNews-Jul-2014.pdf
Date: May 30 to June 2 2014; Chicago, Illinois, USA. Author: Janet Fricker, Medical Journalist.
Data on three separate drugs presented at ASCO underlined the
way immunotherapy is reshaping the treatment of melanoma.
The explosion in treatment is happening across the board, not
just in metastatic melanoma (the combination of nivolumab and
ipilimumab, and pembrolizumab), but also in locally advanced
cutaneous melanoma (PV-10).
In the first study Mario Sznol, from the Yale School of Medicine,
explored the combination of ipilimumab and nivolumab in 94 patients
with inoperable stage II or IV melanoma who had undergone up to
three prior systemic therapies [1].
Nivolumab and ipilimumab are antibody drugs that target and block
two different ‘gatekeepers’ or checkpoints (PD-1 and CTLA-4,
respectively) on T cells, disarming the tumour’s defences against the
immune system and boosting the immune system’s ability to fight
melanoma.
Results showed overall 41% (22 out of 53 patients) responded to
the treatment and 17% (nine) achieved complete remissions.
Furthermore, 42% of the patients had a greater than 80% tumour
reduction by week 36, and responses were durable with 18 of 22
responses (82%) ongoing at the time of the analysis. Across doses, the
one-year and two-year median overall survival rates were 85% and
79% respectively, and the median survival duration 39.7 months.
“Just a few years ago, median survival for patients diagnosed with
advanced melanoma was as little as a year or less, and only
approximately 20-25 % survived two years, so it’s truly remarkable
that we’re seeing a median survival over three years in this trial,” said
Sznol, adding that even in the latest era of targeted and
immunotherapy agents, the median survival is on average about 16-18
months with any new treatment alone.
In the second study Antoni Ribas, from the University of California in
Los Angeles, enrolled 411 patients with metastatic melanoma that had
spread to the skin, lungs or other major organs (221 with prior
ipilimumab treatment and 190 who had not previously received
ipilimumab) to receive pembrolizumab [2].
Pembrolizumab is an investigational, selective, humanized
monoclonal anti-PD-1 antibody, designed to block the interaction of
PD-1 on T cells and to reactivate anti tumour immunity.
The study included seven different cohorts with different eligibility
and three different dosing regimens for single-agent pembrolizumab.
Results showed that overall 34% of patients experienced tumour
response (assessed by Independent Review), including 28% of the 221
patients whose disease had progressed on prior ipilimumab and 40%
of the 190 patients not previously treated with ipilimumab.
The median PFS among ipilimumab naïve patients from all dosing
schedules was 24 weeks (95% CI, 16-48), and 51% achieved 24-week
PFS. The median PFS among the cohort previously treated with
ipilimumab was 23 weeks (95% CI, 14-24), and 44% achieved 24-
week PFS.
“This is probably the biggest phase 1 trial ever conducted in
oncology. We were excited to see that pembrolizumab was effective in
previously untreated patients as well as in those who had multiple
prior therapies, including ipilimumab,” said Ribas.
In the third study, which took place in locally advanced cutaneous
melanoma, Sanjiv Agarwala, from St Luke’s Hospital and Health
Network, Bethlehem, Pennsylvania, explored a subgroup of 54 patients
from a phase 2 study who had most or all of their lesions injected
with PV-10 [3].
PV-10, a 10% solution of Rose Bengal that was originally used as an
agent to stain necrotic tissue in the cornea, has been developed to
selectively target and destroy cancer cells through intralesional
injection, reducing the potential for systemic side effects.
In the original phase 2 study between October 2007 and May 2010,
80 patients with locally advanced cutaneous disease refractory to a
median of six previous interventions, were recruited from seven centres
to receive up to four treatment cycles of injections with intralesional (IL)
PV-10. Furthermore, up to two ‘bystander’ lesions were identified that
underwent biopsy to confirm melanoma, but did not receive treatment.
The current abstract explored the subgroup of patients who had all or
most of their lesions injected, leaving out patients with more advanced
disease where substantial numbers of lesions went untreated.
Results show that for the 28 patients who had all their existing
melanoma lesions injected with PV-10, the overall response rate was
71% (CI 51-87%) with 50% achieving a complete response (CI 31-69%).
Furthermore, when the 28 patients who had all their lesions injected
were analysed together with 26 patients who had two lesions left
untreated (to investigate bystander effects) a complete response was
achieved in 232 of the 363 injected lesions (64%).
“These sub-group analyses show response to PV-10 is maximized
when all lesions get treated. The level of response observed in this
heavily pre treated or refractory patient population with locally
advanced cutaneous melanoma is noteworthy since, unlike those with
more advanced disease, these patients have limited treatment options
now or on the horizon,” said Eric Wachter, the Chief Technology
Officer at Provectus, who co-developed PV-10.
Additionally, data reported from a pilot clinical trial in eight patients
showed that one to two weeks after PV-10 injection patients had
increases in peripheral blood T cells, including CD8+ (p=0.03), CD4+
(p=0.06), CD3+ (p=0.03), and NKT (p=0.05) [4]. “This data provides
a rationale for combination trials of PV-10 with check point protein
inhibitors, such as ipilimumab, pembrolizumab and nivolumab. PV-10
might offer the perfect way to prime the immune system,” said Jeffrey
Weber, the senior author from Moffitt Cancer Center.
Following the presentation Provectus announced that a phase 3 trial
of PV-10 to generate sufficient data for a new drug application (NDA)
is expected to start accrual in the second half of 2014.
References
1. Mario Sznol. “Survival, response duration, and activity by BRAF mutation status
of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) an ipilimumab
concurrent therapy in advanced melanoma. ASCO 2014,
J Clin Oncol 32:5s, 2014 (suppl; abstr LBA9003)
2. Antoni Ribas. “Efficacy and safety of the anti-PD1 monoclonal antibody MK-3475
in 411 patients (pts) with melanoma (MEL).” ASCO 2014, J Clin Oncol 32:5s,
2014 (suppl; abstr LBA9000^)
3. Sanjiv S. Agarwala. “Efficacy of intralesional rose Bengal in patients receiving
injection in all existing melanoma in phase II study PV-10-MM-02.” ASCO 2014,
J Clin Oncol 32:5s, 2014 (suppl; abstr 9027)
4. Amod Sarnaik. "Assessment of immune and clinical efficacy after intralesional PV-
10 in injected and uninjected metastatic melanoma lesions." ASCO 2014,
J Clin Oncol 32:5s, 2014 (suppl; abstr 9028).
Immunotherapy takes centre stage in melanoma |
