(UroToday.com) The 2023 SUO annual meeting included a session on penile cancer, featuring a presentation by Drs. Lance Pagliaro and Curtis Pettaway discussing updates from the InPACT trial. Neoadjuvant paclitaxel, ifosfamide, and cisplatin x 4 cycles is a standard for treatment for high-risk nodal disease and treatment with curative intent. However, there is a need for randomized clinical trial data in the neoadjuvant setting. The goals of InPACT are as follows:
- Collect prospective, unbiased randomized clinical trial data in as many patients as feasible
- Focus on estimation rather than testing hypotheses to reduce the uncertainty about the size of treatment effects
- The primary outcome measure for this trial is survival time from the date of randomization to the date of death from any cause
- Secondary endpoints include: disease specific survival, disease free survival, complications rates, feasibility of surgery after radiotherapy, quality of life, and pathologic complete response rate
The key eligibility criteria for InPACT are (i) histologically-proven penile squamous cell carcinoma, (ii) any T, N1-3, M0, (iii) ECOG performance status <= 2, and (iv) measurable disease (with the exception of biopsy proven N1). Exclusion criteria are: non-squamous or pure verrucous histology, squamous carcinoma of the urethra, any stage M1, prior chemotherapy or radiotherapy, and concurrent second malignancy. The InPACT trial design is as follows:
As follows is an example of InPACT-Neoadjuvant:
Patients with enlarged pelvic lymph nodes at study entry would undergo pelvic and inguinal lymph node dissection, with the following schema for InPACT-Pelvis:
With a target accrual of 200 patients, accrual from 2017 to 2023 has led to 114 patients enrolled in the trial, including 82 from the US and 32 from the UK. The target date for completing patient accrual is May 2024. Dr. Pagliaro concluded this update of the InPACT trial with the following messages:
- Six years after randomizing the first patient, InPACT is much more than a “plus/minus neoadjuvant” trial
- InPACT is historic, given it is the first ever randomized trial in penile cancer with > 100 patients already enrolled and continuing
- Neoadjuvant chemoradiation is a new approach and requires prospective evaluation, which is what InPACT is doing
Dr. Pettaway noted several lessons that have been learned regarding conducting a large international trial in a rare disease. When the InPACT trial was designed in 2011, there were several important questions that were at the forefront of penile cancer management:
- Neoadjuvant therapy – What is the role of neoadjuvant therapy? Does either chemotherapy or chemoradiation provide superior outcomes?
- Treatment of the pelvis – Among patients with prior inguinal lymphadenectomy and adverse features receiving chemoradiation, what is the role of prophylactic pelvic lymph node dissection? Particularly for patients with >=3 positive nodes and extranodal extension and those with bilateral metastases
The InPACT trial is taking a Bayesian approach, with no formal hypothesis testing (initial trial accrual goal of 400 patients globally). This approach does allow for estimating the probability of choosing the better of two therapies in the intention to treat analysis. Overall, this methodology has been accepted for rare cancers if the probability that the true HR is <1, >= 0.6. In the current trial, if HR = 0.80 or less, then the probability of picking the winner is 79% and incorrectly picking a treatment that is inferior is about 10%. Dr. Pettaway noted several challenges at the outset for the InPACT trial:
- Penile cancer is a rare cancer: challenges with regards to accrual and quality of care (surgery, radiotherapy, chemotherapy, radiology, pathology)
- Patients: multiple treatments, multiple randomizations, resources for travel
- Trial complexity: disease stratification (lymph node burden), sites set up for multidisciplinary care (communication, coordination of care, provider teams)
- InPACT leadership: time consuming, infrastructure (credentialing, monitoring, assuring quality)
The goal of site credentialing is to ensure a site’s ability to effectively carry out protocol mandated treatment in a multidisciplinary environment. This includes credentialing for surgeons, radiologists, radiation oncologists, and pathologists. The North American Surgical Oversite Committee (NASOC) states that they “identify sites with interest and capacity for future multi-institutional penile cancer trials.” Additionally, there is ongoing quality assurance, which is submitted within 3 weeks of a procedure: inguinal lymph node dissection checklist, pelvic lymph node dissection checklist, intraoperative photographs, and pathology/operative reports. There is also a NASCO review via monthly meetings with Dr. Phil Spiess.
The InPACT chronology is notable in that it took six years from trial inception to enrollment of the first patient:
Dr. Pettaway also emphasized that there were “unexpected” barriers to accrual:
- The EORTC leadership decided against participating in InPACT given that this trial was not deemed “a priority”, thus a major sponsor was lost
- The UK-EU “BREXIT” in 2016 led to separation of the UK/EU governance, funding, and sponsorship
- A rift in the UK urologic community over study design led to the loss of 3 major centers
- In the USA, there was a delay in accrual secondary to some credentialing challenges
- In Canada, the trial opened but later closed secondary to numerous logistical challenges
In December 2020, after initiating accrual in May 2017, there were only 50 patients accrued, thus in Fall 2021 there was an accrual amendment that led to a new target goal of 200 patients accrued globally, increasing the accrual period to May 2024, with a minimum follow-up period of 2 years. The statistical rationale is as follows:
As of November 2023, there are 114/200 (57%) patients accrued, including 32 at four centers in the UK and 82 at ECOG centers in the US. New sites in 2023-2024 include Vanderbilt University, Rutgers University, University of Arkansas, NCI (Mexico), and Tata Memorial (Mumbai, India).
For the assumed accrual distribution versus actual, Dr. Pettaway provided the following data:
- Question 1a: Neoadjuvant treatment versus surgery alone
- 8/111 (7.2%) of patients: need for 88 patients, 49 events
- Question 1b: Chemotherapy + inguinal lymph node dissection versus chemoradiation + inguinal lymph node dissection
- 72/111 (64.9%) of patients: need 66 patients, 46 events
- Question 2: Pelvic lymph node dissection + chemoradiation versus chemoradiation alone
- 13/111 (11.7%) of patients: need 120 patients, 97 events
Drs. Pagliaro and Pettaway concluded their presentation discussing updates from the InPACT trial with the following take-home points:
- InPACT is the first randomized prospective international trial in penile cancer
- Challenges include penile cancer being a rare disease, InPACT is a complex trial with logistical challenges and required credentialing
- InPACT has had several notable achievements:
- The largest number of patients accrued in a prospective trial of penile cancer
- High quality data (credentialing, ongoing quality assurance)
- Anticipating randomized prospective data comparing neoadjuvant chemotherapy versus chemoradiotherapy (survival outcomes, feasibility, adverse event data)
- Collecting tissue for correlative studies
Presented by:
Lance C. Pagliaro, Mayo Clinic, Rochester, MN
Curtis A. Pettaway, MD Anderson Cancer Center, Houston, TX
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 Society of Urologic Oncology (SUO) Annual Meeting, Washington, D.C., Tues, Nov 28 – Fri, Dec 1, 2023.