FDA Approval Summary: Alpelisib for PIK3CA-related Overgrowth Spectrum (PROS)

Abstract

On April 5, 2022, FDA granted accelerated approval to alpelisib for the treatment of adult and pediatric patients two years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. Efficacy was evaluated using real-world data (RWD) from EPIK-P1 (NCT04285723), a single-arm clinical study in patients two years of age and older with severe or life-threatening PROS who received alpelisib as part of an expanded access program (EAP) for compassionate use. The primary endpoint was confirmed radiological response rate at Week 24 as determined by blinded independent central review (BICR), using volumetric-based criteria given the atypical growth pattern and irregular shape of PROS lesions. Radiological response was defined as a ≥20% reduction from baseline in the sum of measurable target lesion volume in up to three lesions. Of the 37 patients in the efficacy population, 27% (95% CI: 14, 44) had a radiological response at Week 24. Duration of response (DOR) was an additional efficacy outcome measure, and among responders, 60% had a response lasting ≥12 months. Further, supportive clinical documentation suggested early signals of clinical benefit (i.e., improvement in PROS-related signs and symptoms). The most common (≥10%) adverse reactions were diarrhea, stomatitis and hyperglycemia.

Introduction

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term for several ultra-rare clinical entities resulting from somatic activating mutations in the PIK3CA gene that encodes for the p110 catalytic α-subunit of phosphatidylinositol-3-kinase (PI3K) (1). The estimated prevalence of individual subtypes of PROS is less than 1 per million patients, representing less than 5,000 patients in the United States (2). PIK3CA mutations comprise a diverse subset with variable prevalence and distribution among PROS subtypes (3). Affected patients are heterogenous in phenotype, presenting with asymmetric, sporadic overgrowths and vascular malformations that vary in severity from localized with minimal morbidity to extensive and potentially life-threatening. Early-childhood onset of overgrowth is a core feature of PROS. Although growth trajectories of lesions can vary, most patients have a progressive course in childhood that may continue into adulthood (4).

Management options primarily consist of surgical debulking or amputation (although there is a high risk of regrowth), sclerotherapy, endovascular occlusive procedures, off-label use of the mTOR inhibitor sirolimus, and symptomatic treatment (5). Prior to the approval of alpelisib, there were no FDA-approved drugs for the treatment of patients with PROS.

Regulatory History

Alpelisib (PIQRAY) received FDA approval on May 24, 2019, in combination with fulvestrant for the treatment of post-menopausal women and men with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen (6).

In November 2019, alpelisib received Breakthrough Therapy Designation and Orphan Drug Designation for the treatment of PROS. The Type 10 new drug application (NDA) for alpelisib (under a new trade name, VIJOICE) for the treatment of PROS was submitted on October 6, 2021 and included an Assessment Aid to facilitate FDA’s review (7, 8). FDA considered use of a new proprietary name acceptable given the distinct patient population, including pediatric patients, and the non-oncologic nature of PROS (in contrast to adult patients with breast cancer who are treated with PIQRAY). The application was reviewed under the Real Time Oncology Review (RTOR) Program (9).

Nonclinical Pharmacology and Toxicology

Gain-of-function mutations in the PIK3CA gene encoding the catalytic α-subunit of PI3K (p110α) result in aberrant activation of the PI3K/Akt signaling pathway mediating various cellular processes, including cell growth and angiogenesis (10). Alpelisib is a kinase inhibitor of PI3K, predominantly inhibiting the p110α subunit. In vitro, alpelisib exhibited more kinase inhibition in cancer cells harboring PIK3CA mutations than cancer cells expressing wild type PIK3CA. In an inducible PIK3CA-driven mouse model of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal syndrome (CLOVES), a phenotype of PROS, alpelisib attenuated PI3K signaling pathway activity, and this attenuation correlated with preventing the onset of PROS phenotype or improving abnormalities associated with PROS. These alpelisib-related effects in the CLOVES mouse model were dependent on the timing of alpelisib initiation (pre- or post-induction of active PIK3CA), and dose interruption reversed the alpelisib-related effects (11).

Relevant to a pediatric population, in repeat-dose studies in rats, alpelisib caused growth plate thickening and decreased trabeculae of the knee joint, irregular/thinning of dentin and degenerative odontoblasts. These alpelisib-related bone and teeth findings occurred at doses that were approximately ≥ 2 or 0.8 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on body surface area (BSA). Alpelisib induced embryo-fetal toxicities in animals at doses that were approximately ≥ 1.2 or 0.4 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA. Additionally, based on animal findings, alpelisib may impair fertility in males and females of reproductive potential.

Clinical Study Design

The FDA approval of alpelisib is based on data from EPIK-P1, a single-arm clinical study that enrolled eligible patients with severe manifestations of PROS who received alpelisib as part of an expanded access program (EAP) for compassionate use and had available medical chart history. An EAP permits patients with a serious or immediately life-threatening disease or condition to gain access to an investigational medical product for treatment outside of clinical trials when comparable or satisfactory alternative therapies are unavailable (12).

Data for EPIK-P1 were abstracted from medical charts of patients who initiated alpelisib on or before September 23, 2019, at participating clinical sites in five countries (France, Spain, US, Ireland, and Australia). All patients in the EAP meeting inclusion criteria for EPIK-P1 were eligible to participate in the study. Prior to data abstraction, informed consent was obtained, as per local regulations, from eligible patients who were interested in taking part in EPIK-P1.Information was collected from ≤ 24 weeks prior to the index date (the date of alpelisib initiation) up to the data cut-off (DCO). The safety population comprised 57 patients who received alpelisib via an EAP and the efficacy population comprised 37 patients (described in Table 1) who had ≥ 1 target lesion and corresponding radiological imaging.

Table 1:

Demographics and Clinical Characteristics of the Efficacy Population in EPIK-P1

	All Population N = 37 n (%)
Age
Median (range)	14 (2–38)
Age 2–5	8 (22)
Age 6–11	8 (22)
Age 12–17	10 (27)
Adult (18+)	11 (30)
Sex
Female	21 (57)
Male	16 (43)
Ethnicity
Hispanic or Latino	1 (3)
Not Hispanic or Latino	4 (11)
Not reported	22 (59)
Unknown	10 (27)
Country
France	33 (89)
Other (Australia, Spain, US, Ireland)	4 (11)
PROS Subtypes
CLOVES1	30 (81)
MCAP1	3 (8)
KTS	1 (2.7)
FIL	3 (8)
Other	2 (5)
Disease Status
Congenital Overgrowth	34 (92)
Early Childhood-onset of Overgrowth	3 (8)

Source: FDA multidisciplinary review (13).

Abbreviations: CLOVES: Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal syndrome; MCAP: Megalencephaly-capillary maliformation syndrome; KTS: Klippel-Trenaunay syndrome (KTS); FIL: Facial infiltrating lipomatosis

¹Two patients (SUBJID 3000013 and 3000039) have both CLOVES and MCAP subtypes.

The primary endpoint was confirmed response at Week 24 (+/− 4 weeks) by BICR. A response was defined as ≥ 20% reduction in the sum of measurable target lesion volume (1 to 3 lesions) compared to the index date, in the absence of progression of individual target or non-target lesions and the absence of new lesions. Volumetric reduction in target lesion(s) was chosen to determine radiological response rate in EPIK-P1 given the complex growth pattern and irregular shape of PROS lesions. The efficacy analysis included patients with ≥ 1 target lesion and with an imaging scan performed on the index date (or up to 24 weeks prior) for ≥ 1 target lesion. Patients with a missing response assessment at Week 24 were considered non-responders.

Clinical Pharmacology

The recommended adult dose of alpelisib for the treatment of PROS is 250 mg orally once daily. In patients 2 to 17 years old, the recommended starting dose is 50 mg once daily. In pediatric patients ≥6 years old who have received alpelisib for at least 24 weeks, the dose may be titrated to 125 mg daily based on clinical response and may further be gradually titrated to 250 mg daily when the patient turns 18 years old.

Given the nature of the clinical study, no clinical pharmacology data were collected in EPIK-P1; the recommended dosages (50 mg to 250 mg orally once daily) for the treatment of PROS were therefore based on those administered by treating physicians in the EAP and consideration of pertinent clinical pharmacology data included in the original NDA for breast cancer. Pharmacokinetic (PK) modeling simulations predicted the pediatric exposure at the recommended alpelisib starting dose of 50 mg QD is 1/3 of the adult exposure at the recommended dose of 250 mg QD. In addition, the lowest response rate was observed in the 6 – 11 year old age group, which had the highest median baseline target lesion volume among all pediatric subgroups. While nearly half of patients 6 to 17 years old had one or more dose increases during alpelisib treatment, the benefit of a higher dose is uncertain due to the reactive titration strategy in non-responders based on physician discretion. In addition, the sample size of EPIK-P1 is limited and comprised patients with heterogenous PIK3CA mutations and disease subtypes. Given the need for additional data to inform dosage optimization, FDA issued a Postmarketing Commitment (PMC) to study a higher starting dose of alpelisib in PROS patients 6 to 17 years old in a randomized trial to evaluate the comparative PK and clinical outcomes.

Efficacy Results

Baseline characteristics for the 37 patients included in the efficacy population are described in Table 1 (13). In EPIK-P1, the presence of a PIK3CA mutation was determined by local testing (78% NGS, 14% RT-PCR, and 8% other tests) in tissue (81%) or another sample type (19%). To conduct exploratory analyses, Novartis categorized PIK3CA mutations as “frequent” (reported in ≥2% PROS cases in the literature) or “less-frequent” (<2% PROS cases). Approximately 68% of the patients in the efficacy dataset and all patients that attained confirmed responses had “frequent” mutations (Supplementary Table 1 [13]).

The confirmed response rate at Week 24 (+/− 4 weeks) by BICR was 27%. Additional efficacy results are described in Table 2 (14) and Figure 1 (13).

Table 2:

Efficacy Results at Week 24 in EPIK-P1

Efficacy parameters	All patients N=37
Response ratea, b
Responders, n (%)  95% CI	10 (27) (14, 44)
Duration of response (DOR)
Median in months (range)	NR (0.9+, 42.9+)
% ≥ 6 months	70
% ≥ 12 months	60

Abbreviation: +: censored observation.

^aConfirmed response as determined by blinded independent central review (BICR).

^bPatients without any response assessment at Week 24 were considered non-responders.

Source: VIJOICE (alpelisib) [package insert] (14)

Figure 1.

Percent Change in the Sum of Target Lesion Volume (mL) at Week 24 (Efficacy Population). The y-axis represents the percent change from baseline in the volume of target lesions. Each individual bar represents the percent change in the sum volume of target lesion(s) at Week 24. Responders are highlighted in green while non-responders are highlighted in blue. Source: FDA primary review of datasets submitted to NDA 215039 (13).

Safety Results

The safety population of EPIK-P1 consists of 57 patients who received at least one dose of alpelisib a minimum of 24 weeks prior to the established DCO. Approximately 33% of patients received alpelisib for at least two years; review of data collected in EPIK-P1 did not identify new or unexpected safety signals.

The most common (≥ 10%) treatment-emergent adverse reactions (ARs) observed in these 57 patients were diarrhea, stomatitis, and hyperglycemia (Table 3) (13). Laboratory abnormalities worsening from baseline are presented in Supplementary Table 2 (13).

Table 3:

Adverse Reactions (≥5%) in Patients with PROS Who Received VIJOICE in EPIK-P1

Adverse Reaction	All Patients N = 57
	All Grades (%)
Gastrointestinal disorders
Diarrhea	16
Stomatitisa	16
Metabolism and nutrition disorders
Hyperglycemia	12
Skin and subcutaneous tissue disorders
Eczema	7
Dry skin	7
Alopecia	5
Nervous system disorders
Headache	5
Infections and infestations
Cellulitis*	5

Source: FDA multidisciplinary review (13).

DCO: 9 Mar 2020.

Grading according to CTCAE Version 4.03.

No grade 5 ARs occurred.

^aStomatitis: including stomatitis and aphthous ulcer.

^*Note: The only Grade 3 or 4 adverse events in EPIK-P1 consisted of cellulitis in a single patient.

Serious ARs occurred in 12% of patients. The most frequent serious ARs were dehydration and cellulitis, occurring in two patients each. No patients permanently discontinued alpelisib due to an AR. Dosage interruption due to an AR occurred in 11% of patients (ARs requiring dosage interruption in ≥ 2 patients included dizziness and vomiting). Dose reductions due to an AR occurred in 5% of patients (alopecia, memory impairment, and soft tissue infection required dose reduction in one patient each) (14).

Considering the limited size of the safety population and potential limitations given the nature of data collection, product labeling for VIJOICE lists all Warnings and Precautions observed in the oncology population that are contained in the PIQRAY label, even if not observed in EPIK-P1.

Regulatory Insights

This is the first FDA drug approval for the treatment of patients with PROS. The accelerated approval program allows for earlier approval of drugs that treat serious conditions and fill an unmet medical need based on an intermediate clinical endpoint. Substantial evidence of effectiveness for alpelisib in patients with severe manifestations of PROS who require systemic therapy was supported by real-world data (RWD) collected in the EPIK-P1 study. Clinically meaningful and highly durable responses as assessed by BICR were supported by clinical documentation, including information from case report forms (CRFs), photography, and videography, that provided evidence of early signals of improvement in PROS-related signs and symptoms. Additionally, knowledge of the mechanism of action of alpelisib as a kinase inhibitor of PI3K and the natural history of PROS lesions (characterized by lack of spontaneous regression) provide biologic rationale and confidence that observed responses were due to alpelisib.

Key issues arising during review of the application included: 1) acceptability of RWD from an EAP, 2) use of radiographic response rate based on volumetric reduction as a regulatory endpoint in a histologically benign indication, 3) use of supportive efficacy data from physician-reported clinical outcomes data, and 4) the safety of chronic PI3K inhibitor use in pediatric patients.

Real World Data

The FDA defines RWD as data relating to patient health status or the delivery of healthcare routinely collected from a variety of sources (15). Appropriateness of the use of RWD to support substantial evidence of effectiveness depends on the specific clinical context as well as the fit-for-purpose assessment of the data, among other factors. While the data from this application were generated from routine clinical care, patient imaging was evaluated by blinded independent review, significantly reducing the uncertainties (i.e., measurement error and information bias) that often accompany observational studies using real-world data sources.

FDA considered the use of data derived from an EAP to support regulatory decision-making an appropriate approach given the extreme rarity of PROS and its high unmet medical need. The acceptability of data abstracted from medical charts of patients enrolled in EPIK-P1 was supported by the following attributes: a) use of a prospectively defined protocol for data collection and statistical analysis plan, b) use of BICR (as described above), and c) broad eligibility of patients participating in the EAP to reduce selection bias. Additionally, the EAP was designed with predefined eligibility criteria and included guidance for patient enrollment, treatment, and monitoring. Data quality assurance and quality control measures (e.g., standardized data abstraction and data validation) were also implemented.

Volumetric Assessment of PROS Overgrowths

The FDA considers response rate and supportive DOR to be intermediate endpoints that are reasonably likely to predict clinical benefit in patients with severe manifestation of PROS who require systemic treatment for their disease. The response rate of 27% (95% CI: 14, 44) determined by BICR and the durability of responses, including 60% of patients with a response lasting at least one year, observed in EPIK-P1 coupled with the well-characterized safety profile of alpelisib were considered supportive of accelerated approval. To verify and describe the clinical benefit of alpelisib in patients with PROS, FDA issued a PMR for conduct of a multiregional clinical trial in a sufficient number of patients to further characterize response rate, DOR, and clinical outcome assessment (COA) data. Additionally, FDA issued a PMC to obtain data on long-term outcomes of patients with PROS who received alpelisib in EPIK-P1, as chronic administration is anticipated in the intended population.

Supportive Efficacy Data

The FDA reviewed individual case narratives describing clinical outcomes for all 57 patients in EPIK-P1 that were compiled based on information recorded in the patient medical chart and reported in the CRF. These narratives provided detailed patient information, including description of changes in symptoms, function, or medical condition observed during treatment.

Although all radiologic responders in EPIK-P1 had CLOVES and harbored a “frequent” PIK3CA mutation, case narratives documented early signals that alpelisib exerts a treatment effect in patients with PROS subtypes other than CLOVES and “less frequent” PIK3CA mutations. Some notable findings supportive of reduction in PROS-related signs and symptoms with alpelisib in this subgroup include improvements in fatigue, pain, swelling, bleeding, inflammatory flares, ocular function, and mobility.

Preliminary information also indicates that even in patients not demonstrating the pre-defined threshold of volumetric reduction for response, early signals of improvement in signs and symptoms were described, regardless of PROS subtype and PIK3CA genetic mutation. This finding contributed to FDA’s determination of the patient population for the indication statement. To further understand the treatment effect of alpelisib across the genotypic and phenotypic variability observed in PROS, FDA issued a PMR to ensure evaluation of response rate and DOR in patients who have a non-CLOVES subtype and “less frequent” PIK3CA mutation type.

Safety of Chronic PI3K Inhibitor Uses

As PROS will likely require chronic treatment, FDA considered the assessment of safety of prolonged alpelisib use in patients with PROS to be a critical review concern warranting further study. In the context of a severe and potentially life-threatening disease lacking FDA-approved therapies, the overall safety profile of alpelisib was considered acceptable. Importantly, this NDA benefited from an extensive safety database in adult patients with cancer treated with alpelisib. The safety findings in patients with PROS were generally consistent with those observed in the oncology setting, with no new safety signals identified in pediatric or adult patients.

Although the safety data in EPIK-P1 was sufficient to inform a benefit-risk assessment, FDA’s review faced limitations due to the small sample size, retrospective abstraction of safety data collection, and potential variability in safety monitoring across the EAP. Given these limitations, FDA issued a PMR to conduct safety analyses from clinical studies that further characterize the potential serious risk of long-term adverse effects on growth and development in pediatric patients.

Conclusions

The FDA’s favorable benefit-risk assessment of data from EPIK-P1 (Table 4), the strong mechanistic plausibility for effectiveness in PROS, and the well-established safety profile of alpelisib in the oncology setting supported accelerated approval of alpelisib for the treatment of pediatric and adult patients with severe manifestations of PROS who require systemic therapy13. This represents the first FDA approval for patients with this rare and serious nonmalignant disease that can cause significant and progressive morbidity.

Table 4:

FDA Benefit-Risk Summary

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of condition	• PROS is a collection of rare overgrowth disorders resulting from somatic gain-of-function alterations in the PIK3CA gene. • These clinical entities are heterogeneous in both genotype and phenotype but are generally characterized by asymmetric and sporadic lesions that can result in progressive disability. • Tissues in the affected overgrowth can include all or some of the following types: fibrous, adipose, vascular, nervous and skeletal. • The severity of PROS is highly variable, ranging from mild, localized disease to severe, extensive, debilitating, and potentially life-threatening disease manifesting as overgrowths that adversely impact major vessels or critical organs. • PROS-related complications are typically dependent on the size and anatomical location of the lesion and can include organ dysfunction, functional impairment, mobility issues, pain, thromboembolism, hemorrhage, and infection.	PROS is a rare, serious and potentially life-threatening condition.
Current treatment options	• There is a high unmet medical need for patients with severe manifestations of PROS. • There were no FDA-approved drugs for the treatment of PROS prior to the approval. • Management options primarily consist of surgical debulking or amputation, sclerotherapy, endovascular occlusive procedures, off-label use of the mTOR inhibitor sirolimus, and symptomatic treatment.	Prior to the approval of alpelisib in this population, there were no FDA-approved medical therapies for patients with PROS. Safe and effective treatments for this highly morbid condition are needed.
Benefit	• EPIK-P1, a single-arm, clinical study of alpelisib in pediatric and adult patients with PROS who were treated as part of an EAP demonstrated a confirmed radiographic response rate at Week 24 (as determined by BICR) of 27% in an overall efficacy population of 37 patients.	Alpelisib demonstrated clinically meaningful efficacy, including a confirmed radiographic response rate as assessed by BICR that is durable and early signals of benefit in PROS-related clinical morbidities.
	• The majority (60%) of responders had a response lasting 12 months or longer. • In EPIK-P1, a response was defined by at least 20% reduction from the index date in the sum of measurable target lesion volume (1 to 3 lesions), in the absence of progression of individual target or non-target lesions and the absence of new lesions. • Descriptive patient-level data offered preliminary information that alpelisib administration was associated with early signals of clinical improvement in PROS-related symptoms and manifestations.	The FDA accepted volumetric-based response criteria to support the primary endpoint in EPIK-P1 as overgrowths in PROS are complex and irregularly shaped lesions that are less suitable for assessment by traditional response criteria used in solid tumors. A postmarketing requirement (PMR) was issued to further characterize the response rate and durability of response in patients with PROS, following responders for at least 36 months from the onset of response or until disease progression, whichever comes first.
	• Most patients in EPIK-P1 were treated outside of the US.	Based on the limited treatment landscape for PROS and the lack of known differences in PROS biology or epidemiology, it was reasonable to consider the results applicable to the intended use population in the US despite the largely ex-US conduct of the study.
Risk and risk management	• The safety population included 57 patients 2 years of age and older with severe or life-threatening PROS who received doses of 50 – 250 mg orally once daily. The safety review was supported by experience with alpelisib in patients with cancer. • There were no new safety signals identified, and the overall incidence and severity of adverse reactions was low in both pediatric and adult patients. • There may be limitations to the safety data, given the nature of data collection and the relatively small safety database for alpelisib in patients with PROS.	The safety profile of alpelisib is acceptable in view of the severe and potentially life-threatening nature of PROS as a rare disease and the lack of FDA-approved therapies for this patient population. Due to certain limitations in the collection of data in EPIK-P1, product labeling for VIJOICE lists all Warnings and Precautions observed in the oncology setting that are described in the PIQRAY label, including severe hypersensitivity, severe cutaneous adverse reactions, hyperglycemia, pneumonitis, and diarrhea, even if not directly observed in EPIK-P1. PMRs to provide additional data to characterize serious risks of alpelisib in patients with PROS, as well as to further evaluate the safety in pediatric and adolescent patients, were issued.

Source: FDA multidisciplinary review (13).

The FDA considered the confirmed radiographic response rate based on volumetric assessment of lesions by BICR of sufficient magnitude and durability, and the descriptive clinical signals suggesting improvement in overgrowth-related symptoms and disease complications to be supportive of potential clinically meaningful effects. The FDA requested additional response rate and COA data with longer duration of response as a PMR to verify the clinical benefit of alpelisib in patients with PROS. A randomized trial with an initial double-blind, placebo-controlled period with crossover, intended to fulfill the PMR, is ongoing (16). Of note, the randomized and placebo-controlled design of this trial was not requested by FDA; however, randomization to a placebo control was considered acceptable as this study enrolls patients with a spectrum of PROS including those with less severe and less rapidly progressing disease, which is observed in the majority of patients with PROS. Further, while confirmed radiographic responses were not observed in patients with PROS caused by “less- frequent” PIK3CA mutations in EPIK-P1, clinical and nonclinical data suggest that these patients may still derive benefit from treatment with alpelisib, supporting approval of alpelisib for a broader population of patients with PROS. Assessment across mutation subgroups in a subsequent clinical trial is a post-marketing requirement (17).