Robert L. Coleman, MD

Therapies targeting oncogenesis and the tumor microenvironment are increasingly replacing chemotherapies as first-line treatments for non–small cell lung cancer (NSCLC).

 However, in real-world practice, barriers continue to exist for the uptake and use of comprehensive biomarker testing. Whether it is because of long turnaround time frames for molecular testing, payer concerns and a lack of coverage, or another factor, many patients are not receiving the molecular testing they need to initiate targeted therapy early in their cancer care journey. To fulfill the promise of precision medicine for patients with NSCLC, a better understanding of the barriers, challenges, risks, and opportunities around molecular-ly guided therapies for lung cancer is needed.

Recognizing that a large-scale study of the data is needed for deeper insight into targeted therapy adoption, we have formed the MYLUNG consortium to conduct a broad, national, real-world evidence (RWE) study of more than 12,000 patients with NSCLC over a 5-year period. MYLUNG—or Molecularly Informed Lung Cancer Treatment in a Community Cancer Network: A Pragmatic Consortium—will generate real-world practice patterns across The US Oncology Network (The Network) with active surveillance throughout the patient journey. The overall objective of this programmatic study is to identify and proactively address barriers to targeted treatments so patients can obtain necessary molecular testing at the point of diagnosis and receive the right treatment at the right time in their preferred setting of care.

The MYLUNG consortium brings together providers and researchers in The Network, US Oncology Research, and Ontada (all supported by McKesson Corporation), biopharmaceutical manufacturers, and patient advocacy groups in a joint effort to advance precision medicine for lung cancer. It marks a unique level of collaboration among diverse organizations and stakeholders, all working together across the spectrum of NSCLC drug development, therapy, and care.

Supporting more than 480 independent, community treatment center locations across the United States, The Network is poised to address the issues surrounding targeted therapy uptake and use; approximately 55% of newly diagnosed patients are seen in the community setting, and many patients prefer to receive cancer care closest to home.

 MYLUNG highlights McKesson’s ability to integrate a continuous, virtual cycle with feedback loops between the RWE research team and The Network sites of care to quickly integrate best practices across The Network while adaptively responding to the constantly changing landscape of oncology discovery for both diagnostics and treatment.

Meanwhile, biopharmaceutical companies, patient advocacy groups, health care policymakers, payers, and other stakeholders will deepen their understanding of the barriers to care for patients with targetable mutations that may benefit from receiving precision medicine therapies as first-line treatments. With an unprecedented level of engagement among consortium participants, the MYLUNG program will be one of the first broad, prospective, postmarketed research endeavors in lung cancer.

Eighty-four percent of lung cancers are NSCLC, affecting approximately 228,000 patients per year in the US.

Among the 3 main classes of treatments—chemotherapy, immunotherapy, and targeted therapy—the latter category is growing at an exponential rate. Every year, a new crop of targeted therapies is approved for ever-smaller populations of molecularly annotated patients. What was once recognized as 2 NSCLC diseases, squamous cancer and adenocarcinoma, is now about 10 different disease states. We are in an adaptable situation as new mutation discoveries lead to increasingly subdivided tumor types, for which novel therapies are now available.

The FDA has approved several dozen targeted therapies and combinations for NSCLC (eg, ceritinib [Zykadia], bevacizumab [Avastin], osimertinib [Tagrisso], crizotinib [Xalkori], dabrafenib [Tafinlar], pralsetinib [Gavreto], and others). A tremendous amount of bio-pharmaceutical development is ongoing in NSCLC, and the care journey is growing in complexity as providers must navigate an increasingly nuanced world of precision medicine for their patients.

A robust pipeline of double-blind, randomized controlled trials (RCTs) is bringing these new targeted therapies to market, powering a transformation in lung cancer care. Conducted on a specific population of patients who meet eligibility criteria, RCTs produce data that excel at isolating the efficacy and benefit of a specific intervention. However, when a targeted therapy moves into the real world with a heterogeneous patient population, the data often break down because most patients diverge from the trial’s eligibility criteria. The extrapolation of results in RCTs is often very different from patients’ experience with these therapies in the real world.

Although RCTs remain the gold standard in biopharma research, it is crucial to collect RWE through programmatic studies such as MYLUNG, which will interpret the data and generate evidence from thousands of diverse patients. Notably, the purpose of MYLUNG is not to address the comparative effectiveness of different therapies that target the same mutation. Rather, MYLUNG will examine the obstacles to obtaining molecular testing and the decision-making process and timeline that lead a physician to select a treatment for their patient, whether it is chemotherapy, immunotherapy, or targeted therapy.

One such challenge is the molecular-testing timeline, as it can take from 2 to 5 weeks to take a biopsy, send tissue to the lab, and await results and interpretation—always with a risk that a specimen’s quantity or quality will be deemed insufficient or that the data are uninterpretable. Such instances may limit a clinician’s ability to convey information to the patient in a timely way. Oncology practices may implement caregiving interventions—such as using blood assays, tissue navigators, genetic counselors, or process plans—to address hurdles to testing and the uptake and use of targeted therapies. However, practices have little data about such interventions. MYLUNG will change that, drawing on RWE to provide a framework of best practices for providers, based on the heterogeneity of their baseline practice experience.

MYLUNG will consist of 3 protocols, and each will provide value over the 5-year study (

). In protocol 1, the study examines data in structured fields of the electronic health record to discover trends such as the rate of testing, tests selected, and other practice patterns, and it lays the groundwork for the next 2 study protocols. Protocol 2 will observe multiple factors and events that determine which treatment will be utilized as a patient’s first-line treatment. Protocol 3 will connect the dots, enabling prospective, operational interventions—such as choosing blood-based assays over biopsies; utilizing a tissue navigator or genetic counselor; or developing a process plan—to address barriers. The end goal is to improve the rate of appropriate molecular testing and the subsequent assignment of indicated targeted therapies.

In addition to the large size and scope of the study, the innovative potential of MYLUNG lies in its pragmatic approach to finding ways that providers can help patients with lung cancer on a practice level. The Network touches a broad spectrum of diverse patient populations, disease presentations, and needs. Innovation n these areas tends to be slow because interventions are often undertaken within a smaller ecosystem, eg, at a single institution. The sheer scale and diverse ecosystem of MYLUNG will allow it to uncover the most effective interventions that can be broadly implemented and then quickly put into practice. Moreover, beyond helping us answer today’s precision medicine questions, the rich data sets from these studies may help us answer the questions of tomorrow as well.

The benefits of MYLUNG extend to patients, providers, and all manner of stakeholders in lung cancer care. Patients and their advocates want to know that they are receiving the best treatment options available to them in a timely manner. Providers must navigate a landscape of cancer care that grows more complex daily, with novel therapies rapidly coming to market. Biopharmaceutical manufacturers are tasked with developing the targeted medications so oncologists can get the right medicine to the right patient, at the right time. Payers need a better understanding of targeted therapies to determine their cost coverage. And policymakers are tasked with comprehending the potential policy implications of the fast-changing science.

MYLUNG has the potential to significantly impact the way patients with NSCLC are cared for in this dynamic new oncology landscape. Mining a wealth of RWE from each of the 3 protocols, the study investigators will be able to recommend customized approaches and a clear methodology of best practices for providers. The hope is that MYLUNG will positively impact the uptake and use of targeted therapies as first-line treatments where clinically appropriate and, ultimately, lead to improved outcomes for patients with lung cancer.

1. Yuan M, Huang LL, Chen JH, Wu J, Xu Q. The emerging treatment land-scape of targeted therapy in non-small-cell lung cancer. Signal Transduct Target Ther. 2019;4:61. doi:10.1038/s41392-019-0099-9

2. Fact sheet: what is community oncology? Community Oncology Alliance. 2017. Accessed November 17, 2020. https://bit.ly/37Z4hy5

3. Key statistics for lung cancer. American Cancer Society. Updated January 12, 2021. Accessed January 13, 2021. https://bit.ly/34SIBSc

Articles

Therapies targeting oncogenesis and the tumor microenvironment are increasingly replacing chemotherapies as first-line treatments for non–small cell lung cancer. 

MYLUNG Study Explores Molecularly Informed Lung Cancer Treatment 

Oncology is rapidly transitioning into a field where tumor types are increasingly sub-segmented by molecular characteristics, and treatments are becoming structurally informed and designed based not only on tumor characteristics but also patient characteristics. In the conduct of tumor sequencing, multiple alterations are often discovered. However, alignment between molecular alteration and treatment efficacy is still imperfect. Consequently, it is common to use several drugs aimed at various alterations, rather than just 1. Although this approach may be necessary, it increases the complexity of treatment and the possibility of adverse events. 

Much is still unknown about the cancer process and how targeted therapies work on specific tumor vulnerabilities. Providers must closely follow evolving information, especially regarding adverse events. This knowledge will enable them to be proactive to quickly modify treatment and avoid compromising efficacy while keeping the patient on therapy.

Adverse Effects Differ From Chemotherapy 

Chemotherapy as a treatment modality has been used since the 1940s, so its adverse effects are generally well known. Adverse effects caused by targeted therapies can be different from chemotherapy. Some adverse effects are still under appreciated because, in the context of a clinical trial report, they were not fully described due to low frequency and/or prevalence; however, that does not mean that they are harmless. When a targeted agent combines with other drugs the patient is taking, an unexpected adverse effect may appear and be more severe than those caused by chemotherapy.

Many immunotherapy agents can trigger serious problems, such as autoimmune-based adverse events. Providers must respond quickly to manage these conditions. Some of these adverse effects, such as thrombocytopenia, leukopenia, or anemia, may not require management or can be handled in the office. However, a patient with severe diarrhea or pneumonitis who is taking a checkpoint inhibitor can quickly be in a life-threatening situation that requires hospitalization.

Antibody-drug conjugates (ADCs) are an example of how adverse effects of a parent compound might be 

mitigated while new issues arise. ADCs were developed to provide a “targeted” approach to delivering chemotherapy drugs that might otherwise be too toxic to be systemically delivered in its native form. The conjugates leverage tumor cell expression of antigens and/or receptors to focus delivery of a cytotoxic warhead. For the most part, these conjugates are stable in solution and only release their active agent upon binding and internalization at the cancer cell level. However, unique toxicities may occur due to normal cell expression of the same targets or irritation from the conjugate itself.

Today, there are many different types of targeted drugs, and the knowledge base is still being developed concerning adverse events they may cause. Adverse effects largely depend on the type of drug administered and what it targets. The most common adverse effects associated with certain targeted therapies are diarrhea and liver problems, such as hepatitis and elevated liver enzymes (CHECKLIST).

Clinical Trials Leave Many Questions Unanswered 

Even though new targeted therapies may have received FDA approval, little is known about their performance and safety in the broader patient population. Approval in a clinical trial does not mean the drug is right for everyone. Trial populations are relatively small compared with the prevalent population of patients, and documented adverse events may be similarly challenged–particularly since the manner in which adverse events are reported in the medical literature highlights the most common events (usually ≥10%) and the highest degrees of severity. This underestimates the potential burden of less common and less severe adverse events that could have a major impact on treatment tolerance. Extrapolating that data to the real world leaves many unanswered questions. With so many unknowns, bringing these drugs to a broader population is challenging and requires surveillance–a process called pharmacovigilance.

A major difference in a clinical trial’s study population versus the general at-risk population is how the patients on a trial were selected for participation. To reduce the number of confounding variables that could affect the primary efficacy signal, eligibility criteria are outlined to homogenize the study participants. While eliminating patients with preexisting conditions provides a clearer signal, it also effectively reduces extrapolation value, bringing unknown risks to patients not matching those used for the study. Most drug approvals carry a postmarketing commitment to gather data on real-world evidence, and updated safety packages are provided as new data become available. In some cases, this has led to more restrictive general use because the adverse events were more common than anticipated.

Although drug manufacturers do a good job of compiling data about adverse events, much is still unknown. Simply put, health care providers can find themselves in uncharted waters, trying to navigate the safest way for patients to receive potentially lifesaving therapies with limited information. Providers must understand that targeted therapies can potentially affect normal processes in the body and create adverse effects that may be unknown or under appreciated at the time of study closure. Consequently, providers need to be on alert for all symptoms, even if these symptoms are vague or unattributed, as they may ultimately signal the start of an escalating problem.

Comorbidity is very common among patients with cancer. Most commonly, it’s the rule rather than the exception. Among the top 4 incident cancers–lung, colorectal, breast, and prostate comorbidity rates are 52.9%, 40.7%, 32.2%, and 30.5%, respectively.2 These secondary illnesses 

must be managed to ensure patients are healthy enough to withstand treatment. However, it is well documented that some of these medications can complicate the effective delivery of cancer medicines, particularly drugs where natural metabolism is shared.

Continuing education at the provider level is crucial to the effective and safe management of patients with comorbid conditions. Detailed history of concomitant disease and current medication is essential to developing a comprehensive treatment plan. Increasing complexity of both the oncologic and comorbid condition treatment heightens the need for providers to continually update their understanding of new agents and adverse events, utilizing educational opportunities that focus on these new therapies.

Mitigating strategies can be developed based on data that emerge as therapies become more widely used in patients with comorbidities. This approach has been successful with immunotherapy, especially CAR (chimeric antigen receptor) T-cell therapy. As the severity of the adverse effects began to emerge, toxicity guidelines were developed to help providers manage severe autoimmune adverse events, with special attention paid to patients with comorbidities. Today, providers can receive accreditation for delivering CAR T-cell therapy and other complex therapies. As more advanced treatments appear, accreditation may become a reimbursement requirement.

Enabling Successful Treatment Providers can help ensure optimal outcomes for patients undergoing targeted therapies by employing best practices in several key areas, such as:

Patients and providers should be thoroughly educated about known adverse effects. Pharmaceutical companies have done a good job producing materials that provide pretreatment education concerning adverse effects and when to seek help if experiencing difficulties. With immunotherapies, it is critical for patients and providers to understand when symptoms must be immediately addressed and when they can wait. Certain symptoms can worsen in a matter of hours, creating a life-threatening situation.

Closely monitoring patients enables providers to be proactive about adverse events. Many clinical trials today are actually measuring the time to an adverse event and developing a profile for the drug under study. This is a giant step forward in managing symptoms, as it enables providers to create mitigation strategies and understand the natural cadence of adverse events.

There are several approved targeted drugs that require close monitoring because they can cause severe effects outside of the office between cycles, such as hypertension. When this was recognized during trials, home blood pressure cuffs and logs were provided to patients to track their readings. Utilizing this information, a combination therapy was identified that created dangerous adverse effects within the first 2 weeks, enabling providers to proactively manage these symptoms. When the drugs were finally approved, these best practices were brought to the office level to mitigate adverse effects.

Certain PARP inhibitors also require closer monitoring, particularly for platelets and bone marrow suppression. Consequently, weekly counts after the first treatment cycle are required with some of these agents to identify potential problems.

Many practices in The US Oncology Network are using triage and symptom tracking via patient portals to assess degrees of urgency. This real-time communication helps ensure patients get immediate care if needed, minimizing adverse events.

Staying Current Is Challenging But Critical 

The rapid pace of emerging targeted therapies is creating a dynamic world that is increasingly complex for providers. Keeping up with the huge volume of information required to offer these therapies is difficult to manage in addition to patient care responsibilities. Undoubtedly, this will be an ongoing challenge.

The key to success may lie in using all forms of instructive technology and presentations focused on targeted therapies, including social media, webinars, publications, seminars, and other offerings. These educational opportunities enable providers to share real-world evidence and experiences, helping to build a critical knowledge base. As more new agents emerge, every available avenue should be utilized to keep the nuances of these complex therapies top-of-mind for providers so they can deliver safe, expert care.

 1. Targeted cancer therapies. National Cancer Institute. Accessed September 14, 2020. https://bit.ly/2ZQohyl 

2. Pirschel C. The impact of comorbidities on patient care. ONS Voice. January 30, 2017. Accessed September 14, 2020. https://bit.ly/35Ahe0v

Much is still unknown about the cancer process and how targeted therapies work on specific tumor vulnerabilities. Providers must closely follow evolving information, especially regarding adverse events.

Optimizing Benefit in Targeted Therapies Requires Multipronged Educational Approach

chief scientific officer, The US Oncology Network, 

discusses the next steps for tisotumab vedotin following the presentation of findings from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study in patients with previously treated recurrent or metastatic cervical cancer.

This study met its primary end point of objective response rate, which was clinically and significantly improved. Based on this, Coleman says the next step would be to pursue regulatory action, such as an accelerated approval from the FDA. Another next step would be to develop a phase 3 study to evaluate this agent against chemotherapy.

Coleman says an important next step, considering the positive single-agent activity observed in the study, would be to see what tisotumab vedotin could be combined with to improve outcomes further. A number of studies are now ongoing, evaluating potential combinations, such as with immunotherapy or anti-angiogenesis therapy, as well as in different lines and different schedules. This will help to expand our knowledge of the best dosing frequency.

Videos

Robert L. Coleman, MD, discusses the next steps for tisotumab vedotin following the presentation of findings from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study in patients with previously treated recurrent or metastatic cervical cancer.

Evaluating Next Steps for Tisotumab Vedotin in Recurrent or Metastatic Cervical Cancer

Robert L. Coleman, MD, professor of medicine, The University of Texas MD Anderson Cancer Center, explains the rationale for the VELIA trial of veliparib (ABT-888) with frontline chemotherapy and maintenance in patients with high-grade ovarian cancer.

The phase III randomized, placebo-controlled, multinational trial was designed to evaluate the efficacy of veliparib in both the frontline and maintenance phases.

The trial was divided into 3 arms. The first arm received carboplatin and paclitaxel plus placebo followed by placebo maintenance. Arm 2 received carboplatin and paclitaxel plus veliparib followed by placebo maintenance. The third arm was the most significant for improving profession-free survival (PFS) meeting the endpoint of the trial. Patients in this arm received carboplatin and paclitaxel plus veliparib followed by veliparib maintenance.

With the combination of chemotherapy and veliparib, the investigators hoped to show that PARP could augment chemotherapy, Coleman says. The results showed that the addition of veliparib did improve PFS in these patients (23.5 vs 17.3 months in the control arm; HR, 0.68; 95% CI, 0.56-0.83;

Robert L. Coleman, MD, professor of medicine, The University of Texas MD Anderson Cancer Center, explains the rationale for the VELIA trial of veliparib with frontline chemotherapy and maintenance in patients with high-grade ovarian cancer.

Robert L. Coleman, MD | Authors

Articles

MYLUNG Study Explores Molecularly Informed Lung Cancer Treatment

Optimizing Benefit in Targeted Therapies Requires Multipronged Educational Approach

Evaluating Next Steps for Tisotumab Vedotin in Recurrent or Metastatic Cervical Cancer

Rationale for Chemotherapy Plus Veliparib in Frontline Treatment of Ovarian Cancers