Optimal Scheduling of First-Line Therapeutics in Non-Small Cell Lung Cancer

Lead Investigator: Benjamin Schneider, Iowa State University
Title of Proposal Research: Optimal Scheduling of First-Line Therapeutics in Non-Small Cell Lung Cancer
Vivli Data Request: 5880
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

In the United States, lung cancer causes more deaths per year (135,720 estimated for 2020) than does any other type of cancer, and 84% of lung cancer deaths are caused by non-small cell lung cancer (NSCLC) (Siegel et al., 2020). Treatment for NSCLC has expanded greatly in the last century. Early in the 20th century, the primary mode of treatment for NSCLC was surgery, but today we have a large range of therapeutic options available to patients (Jászai & Schmidt, 2019; Liu et al., 2017). An important advancement in oncology was the pairing of chemotherapy drugs (chemical agents which directly attack tumors) and targeted therapy (drugs which precisely target singular mechanisms of tumor proliferation). Between 1996 and 2010, it’s estimated that the percentage of NSCLC patients receiving some combination of targeted therapy and chemotherapy has increased by 20% for stage I/II patients, 28% for stage IIIA patients, and at least 15% for stage IIIB/IV patients (Kaniski et al., 2017). Parallel with advancements in treatments, the prognosis for these patients has also been improving. The 5-year survival rate in NSCLC has advanced from 10.7% in 1973 to slightly less than 21% as of 2019 (Lu et al., 2019). Today, several combinations of chemotherapy, immune checkpoint inhibitors (drugs which prevent cancer cells from evading the immune systems), and antiangiogenics (therapeutics designed to reduce blood flow to tumors) are recommended as first-line therapies for the management of metastatic or recurrent NSCLC (Lung Cancer – Non-Small Cell – Types of Treatment, 2012).

Some patients are burdened with NSCLC that is not affected by chemotherapy. Generally, this phenomenon is called treatment resistance, and in the case of chemotherapy it is called chemotherapy resistance. Chemotherapy resistance that is present at diagnosis is called intrinsic resistance, where chemotherapy resistance that develops over the course of the disease is called acquired resistance. Chemotherapy resistance (intrinsic or acquired) is a regular occurrence in NSCLC. In a 2006 study of resected NSCLC, Thomas A. d’Amato et al. measured significant chemotherapy resistance to carboplatin in 68% of samples, to cisplatin in 63% of samples, and to paclitaxel in 40% of samples – all first-line therapeutics for NSCLC (d’Amato et al., 2006). In the KEYNOTE-001 trial for pembrolizumab (a clinical trial which established the clinical efficacy of pembrolizumab in NSCLC) only 19.4% of patients responded to treatment. The low response rate indicates that most patients did not significantly respond to treatment (Garon et al., 2015). Over a long enough period of treatment, almost all NSCLC becomes broadly treatment resistant (Chang, 2011).

Theoretically, dosages could simply be increased to improve efficacy in cases of treatment resistant NSCLC. However, chemotherapeutics, antiproliferatives, and immune checkpoint inbhibitors have narrow therapeutic windows. This means that the range between a dosage large enough to reduce tumor growth, and small enough to be safe, is small. In cases of acquired or intrinsic resistance to chemotherapy, dosages cannot be easily increased without producing serious adverse effects, including gastrointestinal disturbances, immunosuppression, and anemia (Ahmad & Gadgeel, 2016). Due to both the high side-effect burden and high rate of resistance, NSCLC patients are typically moved to second-line or experimental therapies over the course of their treatment. The majority of NSCLC clinical patients are using drugs still in development (Non-Small Cell Lung Cancer Treatment (PDQ®)–Patient Version – National Cancer Institute, 2020). There is, therefore, a critical need to improve efficacy of both first-line therapeutics and experimental therapeutics to improve therapeutic outcomes, patient survival, and ultimately patient quality of life.

Mathematical modeling and computer simulation of pharmacology (pharmacometric modeling) is an extremely efficient method for optimizing therapeutic efficacy. Pharmacometric modeling does not require the considerable time and resource investment required to conduct a suite of clinical trials in humans. To develop the model, the pharmacometrician can leverage data from multiple studies, involving diverse patient populations, and varying drug combinations and administration schedules, to build a complete mathematical description of the therapeutics and disease. After building the model, it can be used to simulate a series of “what if?” scenarios (e.g. what if the dose was cut in half, but given twice as often?), and to derive the best scheduling and dosing of various therapeutic drug interventions based on the characteristics of the patient.

We have previously published a mathematical model of NSCLC growth dynamics which we used to demonstrate that administering bevacizumab (BEV) and pemetrexed/cisplatin (PEM/CIS) sequentially with a gap of 1 day, rather than concurrently, would improve the efficacy of this combination (quantified as final tumor volume) by more than 50% without the need for increasing therapeutic doses. However, optimal scheduling of this combination in humans has yet to be verified with large sets of clinical data, and the model needs to be extended to explain the behavior of other therapies, including immune checkpoint inhibitors.

Our proposed research consists of two primary aims. First, we expect to use a large set of clinical data to establish a mathematical model to describe tumor growth and response to various drug combinations currently in use for NSCLC (Aim 1). In addition, we expect to determine individual patient characteristics that significantly affect treatment response. This mathematical model will be used to determine the optimal dosing schedule of therapeutic interventions in individual patients with NSCLC (Aim 2). This contribution will be significant as it will broadly and positively impact current healthcare outcomes and clinical therapeutic development in a highly prevalent and largely intractable disease.

Requested Studies:

Randomized, Open-Label, Phase 3 Study of Pemetrexed Plus Carboplatin and Bevacizumab Followed by Maintenance Pemetrexed and Bevacizumab Versus Paclitaxel Plus Carboplatin and Bevacizumab Followed by Maintenance Bevacizumab in Patients With Stage IIIB or IV Nonsquamous Non-Small Cell Lung Cancer
Sponsor: Eli Lilly & Co.
Study ID: NCT00762034
Sponsor ID: 9707

A Single-Arm, Phase 2 Trial of Pemetrexed, Cisplatin,and Bevacizumab as Induction, Followed by Pemetrexed and Bevacizumab as Maintenance, in First-Line Treatment of Nonsquamous Advanced NSCLC
Sponsor: Eli Lilly & Co.
Study ID: NCT01004250
Sponsor ID: 13034

A Randomized, Double-Blind, Phase II Trial of Paclitaxel + Carboplatin + Bevacizumab With or Without PRO95780 in Patients With Previously Untreated, Advanced-Stage Non-Small Cell Lung Cancer
Sponsor: Roche
Study ID: NCT00480831
Sponsor ID: APM4074g

A Randomized, Double-blind Study of the Effect of Avastin Plus Cisplatin and Gemcitabine or Placebo Plus Cisplatin and Gemcitabine on Progression-free Survival in Treatment-naïve Patients With Advanced or Recurrent Non-squamous NSCLC
Sponsor: Roche
Study ID: NCT00806923
Sponsor ID: BO17704

A Randomized, Open-label Study to Explore the Correlation of Biomarkers With Response Rate in Chemo-naive Patients With Advanced or Recurrent Non-squamous Non-small Cell Lung Cancer Who Receive Treatment With Avastin in Addition to Carboplatin-based Chemotherapy
Sponsor: Roche
Study ID: NCT00700180
Sponsor ID: BO21015

An Open Label Study to Assess the Effect of Avastin (Bevacizumab) Combined With First Line Paclitaxel-carboplatin or Second Line Tarceva (Erlotinib) on Progression-free Survival in Non-squamous Non-small Cell Lung Cancer Patients With Asymptomatic Untreated Brain Metastasis
Sponsor: Roche
Study ID: NCT00800202
Sponsor ID: ML21823

A Phase II Trial of Bevacizumab in Combination With First- or Second-Line Therapy in Subjects With Treated Brain Metastases Due to Non-Squamous Non-Small Cell Lung Cancer
Sponsor: Roche
Study ID: NCT00312728
Sponsor ID: AVF3752g

Effects of Two Doses of rhuMAB-VEGF Antibody in Combination w/Chemotherapy in Subjects With Locally Advanced or Metastatic Lung Cancer
Sponsor: Roche
Sponsor ID: AVF0757G

Avastin in Addition to Platinum-based Chemotherapy is Indicated for First-lime Treatment of Patients With Locally Advanced, Metastatic or Recurrent Non-small Lung Cancer Other Than Predominantly Squamous Cell Histology
Sponsor: Roche
Study ID: NCT02596958
Sponsor ID: ML21217

A Randomized, Double-blinded, Placebo-controlled, Multicenter Phase III Study Comparing Bevacizumab Plus Carboplatin/Paclitaxel Versus Placebo Plus Carboplatin/Paclitaxel in Patients With Advanced or Recurrent Non-Squamous Non-Small Cell Lung Cancer Who Have Not Received Prior Chemotherapy For Advanced Disease
Sponsor: Roche
Study ID: NCT01364012
Sponsor ID: YO25404

An Observational Study of Avastin (Bevacizumab) in Combination With Chemotherapy for Treatment of Metastatic or Locally Advanced and Unresectable Colorectal Cancer and Locally Advanced or Metastatic Non-Small Cell Lung Cancer (Excluding Predominant Squamous Cell Histology) (ARIES)
Sponsor: Roche
Study ID: NCT00388206
Sponsor ID: AVF3991n

A Phase II, Multicenter, Single-Arm Study OF Atezolizumab In Patients With PD-L1-Positive Locally Advanced Or Metastatic Non-Small Cell Lung Cancer (BIRCH)
Sponsor: Roche
Study ID: NCT02031458
Sponsor ID: GO28754

A Phase II, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Administered as Monotherapy or in Combination With Bevacizumab Versus Sunitinib in Patients With Untreated Advanced Renal Cell Carcinoma (IMmotion150)
Sponsor: Roche
Study ID: NCT01984242
Sponsor ID: WO29074

A Phase III, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) Compared With Docetaxel in Patients With Non-Small Cell Lung Cancer After Failure With Platinum Containing Chemotherapy (OAK)
Sponsor: Roche
Study ID: NCT02008227
Sponsor ID: GO28915

A Phase II, Multicenter, Single-arm Study of MPDL3280A in Patients With PD-L1-Positive Locally Advanced or Metastatic Non-small Cell Lung Cancer
Sponsor: Roche
Study ID: NCT01846416
Sponsor ID: GO28625

A Phase II, Open-label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of MPDL3280A (Anti−PD-L1 Antibody) Compared With Docetaxel in Patients With Non−Small Cell Lung Cancer After Platinum Failure
Sponsor: Roche
Study ID: NCT01903993
Sponsor ID: GO28753