Summary Basis of Decision for Lartruvo

 

Clinical Pharmacology

Olaratumab, the medicinal ingredient in Lartruvo, is a targeted recombinant human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that specifically binds platelet-derived growth factor receptor-α (PDGFR-α), thereby blocking PDGF-AA, -BB, and -CC binding and receptor activation. The PDGFR-α is expressed on tumour cells and normal stromal cells. Its signalling pathway is important in cancer cell proliferation, metastasis, and the tumour microenvironment. As a PDGFR-α antagonist, olaratumab has been shown in vitro to inhibit the PDGFR-α pathway signalling in tumour and stromal cells. In addition, olaratumab has been shown in vitro to disrupt the PDGFR-α pathway in tumour cells and inhibit tumour growth.

Although olaratumab is capable of binding Fcγ receptors and the C1q complex of complement by virtue of its human IgG1 Fc backbone, its binding to cell-associated PDGFR-α did not elicit an antibody-dependent cellular cytotoxicity response or complement-dependent cytotoxicity response in vitro on a tumour cell line with the highest density of cell surface receptor.

The pharmacokinetic data for olaratumab obtained in four Phase II studies were summarized in a nonlinear mixed-effect population pharmacokinetic model where olaratumab was used at a dose of 15 mg/kg in four different cancer types over three 21-day cycles. The sponsor concluded that the pharmacokinetics of this drug could be well characterized by a two-compartment model with linear elimination from the central compartment and a time to steady-state of approximately 50 days. The model justifies, but it does not predict, that a dose of 15 or 20 mg/kg will reach saturation in the context of target-mediated drug disposition. The nonlinear mechanism, although assumed, could not be incorporated as the usual Michaelis-Menten approximation, since its presence in the model led to numerical instability.

In its current form, the population pharmacokinetic model identifies body weight as a significant covariate for both the systemic clearance and volume distribution parameters and thus justifies the drug dosing on a per weight basis.

Notably, the population pharmacokinetic model differed in its estimation of the terminal half-life of olaratumab by a factor of 2 from the half-life estimate determined in the non-compartmental analysis (NCA). The population pharmacokinetic analysis, when considering the entire therapeutic range, resulted in an estimate of 11 days, whereas after a single dose, the NCA estimate was 6 days. Both half-life estimates were included in the Lartruvo Product Monograph.

For further details, please refer to the Lartruvo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy review of Lartruvo focused on data generated in the Phase II portion of a Phase Ib/II study (JGDG). The Phase II JGDG study was a randomized, open-label, active-controlled study of Lartruvo plus doxorubicin versus single-agent doxorubicin in patients with advanced soft tissue sarcoma whose disease was not amenable to curative treatment with radiotherapy or surgery. A total of 133 patients were randomized 1:1 to treatment with Lartruvo plus doxorubicin (the investigational arm, including 66 patients) or to doxorubicin alone (the control arm, including 67 patients). Of those, 129 patients received at least one dose of study treatment (64 in the investigational arm and 65 in the control arm). Patients in the investigational arm received Lartruvo 15 mg/kg by intravenous infusion on days 1 and 8 of each 21-day cycle. All patients received doxorubicin 75 mg/m² by intravenous infusion on day 1 of each 21-day cycle for up to 8 cycles. Patients in the Lartruvo plus doxorubicin treatment group could continue on single-agent Lartruvo until disease progression, unacceptable toxicity or until any other reason for treatment discontinuation occurred. Patients randomized to receive single-agent doxorubicin were offered single-agent Lartruvo at the time of disease progression.

Patients randomized to receive treatment in this study were required to be 18 years of age or older, have good to moderate performance status (an Eastern Cooperative Oncology Group [ECOG] performance status of 0-2), normal coagulation, normal hepatic and renal functions, suitable heart function (patients could not have had a myocardial infarction within 6 months prior to study entry or unstable angina) and a left ventricular ejection fraction of ≥50%. The study excluded patients who had received prior treatment with an anthracycline, had Kaposi sarcoma, or were pregnant or lactating. Randomization was stratified by PDGFR-α expression (positive versus negative), number of previous lines of treatment (0 versus ≥1), histological tumour type (leiomyosarcoma, synovial sarcoma, and other) and ECOG performance status (0 or 1 versus 2). There were more than 25 soft tissue sarcoma subtypes represented in the study.

The efficacy outcome measures were progression-free survival, objective response rate, and overall survival. The progression-free survival and objective response rate were defined by the Response Evaluation Criteria in Solid Tumours (RECIST) (version 1.1).

Progression-free survival according to investigator assessments was the protocol-defined primary endpoint. Progression-free survival was powered for a one-sided log-rank test at the 0.1 significance level (two-sided p-value = 0.2) commonly used for Phase II studies, but less robust than the traditional two-sided 5% (0.05) threshold typically required for regulatory approval of Phase III studies. The JGDG study met this prespecified endpoint. The combination of Lartruvo and doxorubicin had a reported improvement of 2.5 months in the median progression-free survival over doxorubicin alone (6.6 versus 4.1 months) with an unstratified hazard ratio (HR) of 0.730 (95% CI: 0.494, 1.079; two-sided p-value = 0.12).

No statistically significant differences were observed in objective response rates between the investigational arm (18.2%) and the control arm (11.9%), although a trend for higher response rates was observed for patients treated with Lartruvo. Confirmed response rates were 15% (10/66) and 9% (6/67) in the investigational and control arm, respectively.

The combination of Lartruvo and doxorubicin gave rise to a statistically significant improvement of 11.8 months in median overall survival compared to doxorubicin alone (unstratified HR = 0.52 [95% CI: 0.34, 0.79]; p = 0.0017), corresponding to a 48% reduction in the risk of death. The median overall survival was 26.5 months (95% CI: 20.9, 31.7) in the investigational arm compared to 14.7 months (95% CI: 9.2, 17.1) in the control arm. This finding points to a large benefit of adding Lartruvo to the standard-of-care doxorubicin in the treatment of soft tissue sarcoma patients. These results, however, are only considered promising and not substantive evidence of efficacy because of limitations resulting from small numbers of patients enrolled in a heterogeneous disease population with some imbalances noted between the two arms in soft tissue sarcoma subtypes. Therefore, Lartruvo, in combination with doxorubicin, meets the qualifications for market authorization as per the Notice of Compliance with Conditions (NOC/c) Guidance. A larger Phase III study is ongoing to address the limitations identified in the Phase II study and to establish the therapeutic benefit of Lartruvo, in combination with doxorubicin, in patients with soft tissue sarcoma (see What follow-up measures will the company take?).

Indication

The New Drug Submission for Lartruvo was filed by the sponsor with the following indication:

Lartruvo (olaratumab) is indicated:

• In combination with doxorubicin for the treatment of patients with advanced soft tissue sarcoma (STS) not amenable to curative treatment with radiotherapy or surgery.

To ensure safe and effective use of the product, Health Canada revised the proposed indication to more accurately reflect the target patient population. A caveat statement was also added to the indication, providing details regarding the limitations of the currently available data. Accordingly, Health Canada approved the following indication:

Lartruvo (olaratumab) is indicated:

Approval was based on an overall survival benefit demonstrated in a Phase II study. Description of clinical benefit needs to be verified in a confirmatory Phase III trial.

• In combination with doxorubicin for the treatment of adult patients with advanced soft tissue sarcoma (STS) not amenable to curative treatment with radiotherapy or surgery and for whom treatment with an anthracycline-containing regimen is appropriate.

For more information, refer to the Lartruvo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Lartruvo was evaluated on the basis of data derived from 64 patients with advanced soft tissue sarcoma who were enrolled in the randomized Phase II Study JGDG, an active-controlled trial (described in the Clinical Efficacy section) comparing Lartruvo plus doxorubicin with single-agent doxorubicin.

Patients treated with Lartruvo and doxorubicin experienced more events of neutropenia compared to the patients treated with single-agent doxorubicin. The most common adverse reaction leading to dose reduction was Grade 3 or 4 neutropenia (20%). The most common adverse reaction resulting in dose delays, which occurred in 52% (33/64) of patients, was neutropenia (33%). The increased risks for neutropenia, both in terms of incidence and severity, for the combination therapy compared to doxorubicin alone were included in the Warnings and Precautions and Adverse Reactions sections of the Lartruvo Product Monograph.

There were also more reports of musculoskeletal pain (a composite of the preferred terms: arthralgia, back pain, bone pain, flank pain, groin pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity) in the investigational arm (64.1%) compared to the control arm (24.6%).

The most serious Lartruvo adverse reactions were infusion-related reactions. There were four serious hypersensitivity/anaphylaxis reactions in the Phase II JGDG study. They occurred within 10 minutes after the start of the first Lartruvo infusion and required immediate attention including prolonged hospitalization, with one case resulting in death. Notably, the risk of anaphylactic reaction is associated with elevated IgE antibody levels against galactose-α-1-3-galactose. A Serious Warnings and Precautions box was included in the approved Lartruvo Product Monograph to highlight the serious and life-threatening nature of infusion-related reactions.

Overall, the safety profile of Lartruvo, when used in combination with doxorubicin, is considered acceptable for adult soft tissue sarcoma patients with advanced disease not amenable to curative therapy with radiation therapy or surgery and for whom treatment with an anthracycline regimen is appropriate. Appropriate warnings and precautions are in place in the approved Lartruvo Product Monograph to address the identified safety concerns.

For more information, refer to the Lartruvo Product Monograph, approved by Health Canada and available through the Drug Product Database.