NeuVax is a peptide-based vaccine, under development by Galena Biopharma (NASDAQ:GALE), which aims to prevent recurrence of breast cancer in women who have undergone standard of care therapy, including surgery, radiation and chemotherapy. It is the lead drug in Galena's pipeline of cancer immunotherapy and hematology agents. The Special Protocol Assessment or SPA agreement with the FDA for the current NeuVax study specifies a minimum 30% efficacy (i.e., reduction in relative risk of recurrence) for approval. The Phase 3 NeuVax PRESENT trial calls for an Early Interim Analysis after the 70th event - the possible outcomes include a halt for futility, proceed with modifications, or unconditional proceed. If Galena proceeds, the study will reach its primary efficacy endpoint in April 2018 after a three-year follow-up of the last enrolled patient. This represents the roadmap for approval of NeuVax.
Galena is a biopharmaceutical company with all the attendant issues of an extended timeframe without commercial revenue and high development costs. The current balance sheet cash position for Galena is $38.2 M as of February 29, 2016 with a quarterly burn rate of $9 M to $11 M (Year-End 2015 Earnings Conference Call). With the settlement of overhanging shareholder derivative and securities class action lawsuits, a major remaining downside risk is the possible failure of its drug pipeline, especially NeuVax. In the balance, a successful PRESENT trial and subsequent FDA approval of the first-in-class NeuVax vaccine point to annual sales in the U.S. market alone of greater than two billion dollars (Galena presentation February 8, 2016).
Slide from Galena-Presentation-8-Feb-16.pdf
In January of this year I published two articles, "NeuVax Vaccine: A Matter of Signal Integrity" and Part 2. The goal of the series was to develop a model of the Phase 3 NeuVax PRESENT trial in order to provide perspective to the upcoming interim analysis now anticipated in Q2 2016. The analysis was data driven and made with as few underlying assumptions as possible. To address some thoughtful concerns from readers, I present the following addendum. In particular, I intend to address the issue of predicting the baseline recurrence rate of breast cancer for women in the current PRESENT study.
The original analysis was only constrained by the NeuVax Phase 1/2 data and made no assumptions about the baseline control group of women with breast cancer. The Phase 1/2 trial evolved from a Phase 1/2 dose escalation/schedule optimization study (NCT00841399) followed by a Phase 1/2 study with optimal dose and schedule (NCT00854789), and a later voluntary booster program added by amendment. As a consequence of this process, the final target patient population represents a small fraction of all the women volunteers in the study; in particular, the node-positive HLA-A2/3+ HER2 1+/2+ control arm consists of only twenty-seven patients. This small sample size presents the problem of uncertainty in the individual data points (granularity) - one patient out of twenty-seven amounts to an uncertainty of +/- 3.7% per data point on the Kaplan-Meier chart.
A larger issue is how the NeuVax Phase 1/2 women with breast cancer compare with the current Phase 3 PRESENT trial volunteers with respect to their hazards of recurrence under current standard-of-care treatment. The first Phase 1/2 study started in July 2001, while the second study started in December 2002; enrollment for both studies was complete by March 2009. A significant therapeutic advancement during this period was the introduction of anti-HER2 agents (see Comparison of Breast Cancer Recurrence and Outcome Patterns Between Patients Treated From 1986 to 1992 and From 2004 to 2008, Cossetti et al., J Clin Oncol 33: 65-73). Trastuzumab (Herceptin) was approved by the FDA on September 25, 1998 and has a range in efficacy (i.e., reduction in relative risk of recurrence) of 33% to 52% in four pivotal trials (source). A key observation is trastuzumab has not been shown to benefit women whose breast cancer lacks HER2 overexpression or gene amplification (Seidman et al., J Clin Oncol 26: 1642-1649). Since the target patient population includes only women with HER2 low- and intermediate-expressing tumors (IHC 1+/2+), the findings from the Phase 1/2 studies should directly carry over to the current PRESENT trial. This should also be the case with respect to chemotherapy and endocrine therapy since the Phase 1/2 volunteers, like current patients, extensively utilized both modalities (82% received chemotherapy, while 91% received endocrine therapy for hormone receptor-positive tumors).
Data from a more recent study, "Phase II Trial of the HER2/Neu Peptide GP2 + GM-CSF Vaccine vs. GM-CSF Alone in HLA-A2+ OR the Modified HER2/Neu Peptide AE37 + GM-CSF Vaccine vs. GM-CSF Alone in HLA-A2- Node-Positive and High-Risk Node-Negative Breast Cancer Patients" (NCT00524277, started January 2007), helps confirm the similarities between NeuVax Phase 1/2 volunteers and the current group of women in the PRESENT trial (enrolled from January 2012 to April 2015) and reduces the uncertainty in the Disease-Free Survival or DFS curve through diversification. The final pre-specified analysis of AE37 was reported at the 2015 ASCO Annual Meeting and details 60-month DFS data for the node-positive HLA-A2- GM-CSF-only control group (enrolled from 2007 to 2010). The primary analysis of GP2 was reported at the 2014 Breast Cancer Symposium and details 34-month median follow-up DFS data for the node-positive HLA-A2+ GM-CSF-only control group (enrolled from 2007 to 2013). The data is summarized above and aggregate data shown in red (RRR = Relative Risk Reduction, CG = Control Group, LE = HER2 Low Expression, OE = HER2 Overexpression). As can be seen, women with HER2 overexpressing tumors (associated with more aggressive disease and poorer outcomes in the pre-Herceptin era, see Witton et al., J Pathol 2003 Jul; 200(3): 290-7) have markedly better DFS rates than HER2 low-expressors because of the advent of modern anti-HER2 agents. The overall trends stay consistent through time, and the HER2 low-expression control group aggregate data confirms the original 36-month and 60-month data points are reasonable estimates of the actual DFS curve.
A revised fitted hazard function and corresponding recurrence curve for the NeuVax PRESENT trial model is shown in red. The least specified data point from the original analysis appears to be the 81.5% DFS rate at 20 months; however, the historical 82.8% DFS data point is well within the uncertainty of that original value. The historical Stage II hazard function from Cheng et al. is also noteworthy because it is based on women diagnosed between 1991 and 1997, the pre-Herceptin era - this hazard function is not an unreasonable approximation for the early recurrence rate of the HER2 low- to intermediate-expressing PRESENT trial control group. While it may be tempting to lower the peak hazard rate, doing so creates a much sharper bend at the 20-month or 36-month DFS mark and deviates significantly from the behavior of all published DFS curves for women with breast cancer.
This chart shows the final enrollment curve and revised projected breast cancer recurrence curves. The 78% efficacy recurrence curve, equivalent to the Phase 3 Target Patient Population efficacy, now crosses the 70th event threshold in December 2015, while the 100% efficacy recurrence curve now crosses that threshold in May 2016. Dr. Mark Schwartz, President and CEO of Galena, has publicly stated that the 70th breast cancer recurrence event is now expected in late March or early April 2016 (Year-End 2015 Earnings Conference Call, March 10, 2016) - this corresponds to a mean efficacy of 95% or greater in the current simulation model. While this forecast is slightly less aggressive than the original analysis, it derives from a broader and more suitable base and does not require a 2% increase in peak hazard rate to fit the baseline breast cancer DFS rate for the current PRESENT trial. As an independent and unambiguous corroboration of the positive course for the trial, Bijan Nejadnik, Executive Vice President and Chief Medical Officer of Galena Biopharma, announced on the Year-End 2015 Earnings Conference Call that "the overall rate of occurrence is very much in line in what has been expected previously."
To avoid the Flaw of Averages (à la Dr. Sam Savage), the NeuVax PRESENT trial model was used to generate the revised distribution of all possible dates for the 70th breast cancer occurrence event. The value of this exercise is to generate all permutations of recurrence in the treatment and control arms which sum to 70 events - this approach accounts for the possibility of better-than-expected performance from the control arm.
A 70th breast cancer recurrence event in late March 2016 thus predicts (1) no possibility of NeuVax efficacy equaling 30% or less (the minimum Special Protocol Assessment threshold required for approval by the FDA), (2) no possibility of NeuVax efficacy equaling 50% or less, (3) a 21% chance of NeuVax efficacy between 51% and 78%, and (4) a 79% chance of NeuVax efficacy greater than 78%. This indeed is still a strong and highly encouraging signal!
In closing, I hope I have further increased the signal-to-noise ratio so you too can clearly appreciate the signs of a successful Phase 3 NeuVax vaccine PRESENT trial. The stakes in our pre-NeuVax era are tangible: Each and every day, forty American women experience the soon-to-be preventable nightmare of their breast cancer recurring, and twenty-five of them will not survive this horrible fate. NeuVax is a game changer which promises to lift the odds for disease-free breast cancer survival and help these women live rich and full lives.
David M. Fujii, M.D.
Pediatric Cardiac Anesthesiologist and Electrical / Mechanical / Aeronautics & Astronautics Engineer
Disclosure: I am/we are long GALE.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
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