Nathan A. Pennell, MD, PhD, an associate professor in the Department of Medicine and director of the Lung Cancer Medical Oncology Program at the Taussig Cancer Institute of Cleveland Clinic, discusses the importance of understanding the cost-effectiveness of osimertinib (Tagrisso) in non–small cell lung cancer (NSCLC).

During the 2021 ASCO Annual Meeting, findings from a cost-effectiveness analysis of adjuvant osimertinib in patients with resected, 

-mutant NSCLC were presented. The results demonstrated that adjuvant osimertinib is cost-effective if one is willing to pay $317,119 more per quality-adjusted life years–gained. 

Currently, osimertinib is approved by the FDA for use in this patient population and is often covered by insurance, says Pennell. However, in countries other than the United States, cost-effectiveness may be considered more often as a determinant in treatment selection, Pennell explains. 

As such, treatment with osimertinib should not be considered cost-ineffective, but it is important for providers and patients to understand the cost of treatments, such as osimertinib, in all situations, concludes Pennell.

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Nathan A. Pennell, MD, PhD, discusses the importance of understanding the cost-effectiveness of osimertinib in non–small cell lung cancer.



Dr. Pennell on Understanding the Cost-Effectiveness of Osimertinib in NSCLC

Nathan A. Pennell, MD, PhD, an associate professor in the Department of Medicine and director of the Lung Cancer Medical Oncology Program at the Taussig Cancer Institute of Cleveland Clinic, discusses remaining challenges in non–small cell lung cancer (NSCLC).

Tremendous progress has been made in the NSCLC space over the past decade, says Pennell. There have been several new discoveries in terms of targeted therapies for patients with 

Although immunotherapy has been practice changing, it is effective in a minority of patients with metastatic disease. Therefore, research is needed to enhance the efficacy ​of this modality.

To that end, research is focused on ​developing novel immunotherapy combinations​, as well as personalizing treatment through the use of T cells, ​says Pennell.

In addition to evaluating novel agents, the field should focus on ​improving access to currently available therapies as recent studies have shown that less than half of patients with targetable genetic alterations are identified and treated appropriately, Pennell concludes. 

Nathan A. Pennell, MD, PhD, discusses remaining challenges in non–small cell lung cancer.

Dr. Pennell on Remaining Challenges in NSCLC 

Nathan A. Pennell, MD, PhD, an associate professor in the Department of Medicine and director of the Lung Cancer Medical Oncology Program at the Taussig Cancer Institute of Cleveland Clinic, discusses the evolution of targeting HER2 in lung cancer.

HER2 is a target that has been around for a long time because it is used routinely in the treatment of patients with breast cancer, says Pennell. In lung cancer, it has been recognized that 

 mutations in the HER2 tyrosine kinase domain have been present in the disease for a long time; roughly 2% of lung adenocarcinomas have 

Unfortunately, the current data on targeting HER2 have proven to be disappointing, according to Pennell. TKIs that target EGFR and HER2, such as afatinib (Gilotrif), have had trials, but have demonstrated relatively marginal efficacy and an effect that is short lived. However, that seems to have changed recently with the emergence of the antibody-drug conjugates (ADCs).

ADCs have shown demonstrated promising efficacy in phase 2 trials with 

-mutant lung cancer. Over the past few years, some trials examining these agents in lung cancer have been presented at medical meetings. For example, findings from a phase 2 trial with ado-trastuzumab emtansine (Kadcyla; T-DM1) were reported, and this agent is already available for use in HER2-positive breast cancer. The agent was examined in a cohort of patients with 

-mutant lung cancer and was found to elicit an impressive overall response rate of 44% with a promising duration of control, says Pennell. This agent was probably used off label for HER2-positive lung cancer after these data were presented, Pennell adds.

Then, an oral presentation was delivered during the 

 on the phase 2 DESTINY-Lung01 trial, which evaluated the ADC fam-trastuzumab deruxtecan-nxki (Enhertu) in 

-mutated lung cancer. The agent showed an impressive response rate of 61.9%, which is comparable with what is expected with other EGFR inhibitors in 

-mutant lung cancer. Trastuzumab deruxtecan also had an estimated progression-free survival of 14 months. For the first time, the field is starting to see targeted drugs for this patient population that mirror targeted drugs that have been developed for other molecular alterations in lung cancer, concludes Pennell.

Nathan A. Pennell, MD, PhD, discusses the evolution of targeting HER2 in lung cancer.

Dr. Pennell on the Evolution of Targeting HER2 in Lung Cancer

Nathan Pennell, MD, PhD, an associate professor in the Department of Medicine and director of the Lung Cancer Medical Oncology Program at the Taussig Cancer Institute of Cleveland Clinic, discusses the evolution of targeted therapies in the field of non–small cell lung cancer (NSCLC).

Ten to 15 years ago, NSCLC was still being treated as a single disease where every patient received chemotherapy, says Pennell. Then, with the discovery of activating mutations in the abnormal growth factor receptor, the era of targeted therapies and molecular testing for lung cancer began.

Over the past few years, this movement has accerlated. Now, several different molecular alterations within nonsquamous NSCLC or adenocarcinoma of the lung are being tested for, says Pennell. In May 2020, 2 new drugs were approved for patients with 

The guidelines issued by the College of American Pathologists still recommend testing for 

 alterations, even though since 2018 there drugs have also been approved for patients with 

 V600E–mutant disease. Then, with the addition of 

 fusions and MET aberrations, there is a wide range of available FDA-approved options for different patient populations. 

 fusions have also emerged; these aberrations are very rare but still have effective treatment options available if they are identified, explains Pennell. 

With all of these changes, patients must be educated to speak with their providers about available options. Oncologists must also stay educated on emerging data, according to Pennell. If genetic alterations are not identified, patients run the risk of receiving suboptimal treatment for their disease, concludes Pennell.

Nathan Pennell, MD, PhD, discusses the evolution of targeted therapies in the field of non–small cell lung cancer.

Dr. Pennell on the Evolution of Targeted Treatment in NSCLC

Nathan Pennell, MD, PhD, a medical oncologist and director of the Lung Cancer Medical Oncology Program at the Taussig Cancer Institute of Cleveland Clinic, discusses challenges with next-generation sequencing (NGS) in lung cancer.

Part of the challenge with access to next-generation sequencing (NGS) in the lung cancer space is inertia, says Pennell. Some institutions already have single-gene testing in place, although many do not know what tests their pathology department specifically uses. Many times, tests are sent out to external vendors that utilize different testing techniques. However, NGS should be broadly available—especially in lung cancer, Pennell emphasizes.

Multiple FDA-approved vendors and assays are available within the space that can look for all of the guideline-suggested targets. As such, access to NGS should no longer be a barrier, says Pennell. However, other barriers to using NGS exist, such as having enough tissue and ensuring that there is sufficient turnaround time in order to inform decisions on how to treat patients. 

There is work to be done, not just in raising awareness of this approach, but also ensuring that institutions have the right infrastructure in place to provide testing to all eligible patients and to receive the results in a timely fashion. The truth is that there is no reason that NGS should not be universally used in lung cancer, concludes Pennell.

Nathan Pennell, MD, PhD, discusses challenges with next-generation sequencing in lung cancer.

Dr. Pennell on Challenges With NGS in Lung Cancer

Nathan A. Pennell, MD, PhD, director, Lung Cancer Medical Oncology Program, Taussig Cancer Institute, Cleveland Clinic, discusses the considerations when choosing therapy for patients with lung cancer who need immediate therapy but have not received the results of their molecular testing.

Sometimes in practice, patients diagnosed with lung cancer have received PD-L1 assay results but not molecular testing results because genomic testing takes longer to process, explains Pennell. In other scenarios, there may not be enough tissue for molecular testing. To avoid the situation, Pennell recommends trying to streamline the process within the institution and incorporate plasma testing for faster results.

If patients need to start therapy before receiving the molecular testing results, treatment options need to be considered carefully. The consequence of missing an oncogenic driver can be significant and cause the patient to miss out on potentially life-saving therapy, says Pennell. Patients with oncogenic drivers are much more likely to benefit from immunotherapy versus patients without drivers. If a patient is later found to have a molecular driver but first receives immunotherapy, they must wait months before the drug exits their system, concludes Pennell.

Nathan A. Pennell, MD, PhD, discusses the considerations when choosing therapy for patients with lung cancer who need immediate therapy but have not received the results of their molecular testing.

Dr. Pennell on Considerations for Immediate Treatment in Lung Cancer

Nathan A. Pennell, MD, PhD, director, Lung Cancer Medical Oncology Program, Cleveland Clinic Taussig Cancer Institute, discusses the benefits of liquid biopsies in lung cancer.

Plasma testing for genetic variations can be helpful in scenarios where the patient does not have enough tissue for tissue testing or the wait for tissue testing results is a significant amount of time, explains Pennell. In Pennell’s practice, it is common for patients to have a tissue biopsy as well as a biopsy from somewhere else. In his practice, Pennell and his team do not have access to the tissue immediately because protocol is through the pathology department and the tissue is mailed to him, creating a wait time of weeks or a month to get results from tissue. In that setting, performing a liquid biopsy is helpful.

Plasma testing along likely cannot replace tissue testing, though its positive results are reliable, says Pennell. If a liquid biopsy shows a positive result for a mutation or gene fusion, that can be used to proceed to treatment. In common mutations like 

 where patients likely do not have another actionable mutation, patients can proceed to systemic chemotherapy or immunotherapy. Plasma testing is going to miss about 20% of actionable mutations, which means if the plasma testing gives a negative result, the tissue test must be consulted, according to Pennell. If treatment must be started before the molecular testing results are received, Pennell suggests starting with chemotherapy alone.

Nathan A. Pennell, MD, PhD, discusses the benefits of liquid biopsies in lung cancer.

Dr. Pennell on Benefits of Liquid Biopsies in Lung Cancer

Nathan A. Pennell, MD, PhD, director, Lung Cancer Medical Oncology Program, Cleveland Clinic Taussig Cancer Institute, discusses the underutilization of genetic testing in lung cancer.

Genetic testing is not used as commonly as it should be, says Pennell. Approximately 70% to 80% of patients in the United States are being tested for 

 mutations, and less than half of patients with advanced disease are being tested for other mutations, Pennell adds. Additionally, the majority of patients are still getting single-gene tests rather than comprehensive next-generation sequencing. Patients are being tested for 

 sequentially rather than at the same time, and it doesn't cost much more to test for every actionable gene than it does to test for a single actionable gene, explains Pennell. Notably, sequential testing becomes more difficult after the first couple of tests because there's a significant drop-off in the availability of tissue with which to perform the testing, adds Pennell.

A publication from the University of Colorado reported that the median survival of patients with 

-positive disease at their institution ranged from 7 and 8 years. Moreover, Pennell has a patient with 

-positive NSCLC who is now 11 years out from their diagnosis on targeted therapy. Such outcomes would not be possible without the use of genetic testing. To account for these mutations, patients should undergo reflex testing at the time of their diagnosis, Pennell concludes.

Nathan A. Pennell, MD, PhD, discusses the underutilization of genetic testing in lung cancer.

Dr. Pennell on the Underutilization of Genetic Testing in Lung Cancer

Reflecting on the past 20 years of advances in non—small cell lung cancer (NSCLC), I am struck by how long a period went by with so little progress. Of course, today NSCLC treatment is changing at a breakneck pace, with new advancements presented at seemingly every major meeting and newly approved drugs emerging multiple times per year. However, not that long ago, NSCLC treatment was anything but exciting, and it took a completely different way of thinking about this disease to make today’s advances happen.

In 1999, the data supporting routine use of platinum-based chemotherapy were still fresh, based on a meta-analysis of chemotherapy trials showing a modest survival benefit with these regimens.

 Prior to that, there really was no proven therapy for advanced NSCLC if it wasn’t resectable or amenable to radiation. In fact, the name “non—small cell” itself reflects the recognition at the time that the only value in a diagnosis of NSCLC was to rule out the more treatable small cell carcinoma (No, I’m not kidding.)

The understanding that platinum-based chemotherapy was beneficial led to a flurry of studies, culminating in 2002 with the ECOG 1594 trial,

 which showed that all platinum-doublet regimens were equivalent in NSCLC, with a response rate of 19% and median survival of 8 months. It was clear by then that new strategies would be needed to move the field forward and that treating everyone the same meant that just a few people experienced benefit.

Over the next decade the field saw multiple new targeted agents enter the fray, and for the first time a diagnosis of “non—small cell carcinoma” was no longer good enough. We needed to know at least if it was squamous cell carcinoma or adenocarcinoma for both safety

 reasons. We had our first evidence that genetic subtypes of lung adenocarcinoma existed with the discovery of 

 and that these types of tumors benefited from up-front genetic testing because targeted treatments worked much better than one-size-fits-all chemotherapy.

 In the most recent decade—really, the past 6 to 7 years&mdash;we have seen an acceleration of discovery in NSCLC, primarily driven by our understanding that there are many types of lung cancer. Ubiquitous pie charts split NSCLC into multiple pathologic, genetic, and biomarker-defined groups that now must be determined before a course of therapy can be chosen. At least 4 genetic tests (

) should be run on every lung adenocarcinoma case, with more waiting in the wings (I see you, 

). PD-L1 immunohistochemical testing identifies which patients would benefit from immune checkpoint inhibitors as monotherapy or if combination chemoimmunotherapy would be the best choice.

Who could have foreseen in 1999 that in 2019 essentially no patient with NSCLC should receive chemotherapy alone as their optimal choice of therapy?

Whether you call it precision medicine or personalized therapy, this approach has led to real hope of lasting benefit for many patients with NSCLC. In 2019, a new patient with stage IV 

-positive adenocarcinoma can expect to live a median of 3 to 5 years,

 and the 30% of patients with >50% PD-L1 expression have a median survival of 30 months with pembrolizumab (Keytruda),

 with some living beyond 5 years and possibly being cured. We still have a long way to go, but at the current pace of discovery I can’t wait to see what the next 20 years hold!

Non-small Cell Lung Cancer Collaborative Group. 

Articles

In the most recent decade, we have seen an acceleration of discovery in NSCLC, primarily driven by our understanding that there are many types of lung cancer.

From One Cancer to Many: How NSCLC Treatment Has Changed in 20 Years

Nathan A. Pennell, MD, PhD, director, Lung Cancer Medical Oncology Program, Cleveland Clinic Taussig Cancer Institute, discusses the cost-effectiveness of next-generation sequencing (NGS) for patients with metastatic non—small cell lung cancer (NSCLC).

A study presented at the 2018 ASCO Annual Meeting reported that using NGS in the screening of patients with metastatic NSCLC can save Center for Medicare and Medicaid Services payers $1.3 million to $2.1 million. The economic impact of NGS compared with sequential single-gene testing modalities to detect genomic alterations in patients with metastatic NSCLC was tested using a decision analytic model. Included in the study were 1 million hypothetical newly diagnosed patients with Medicare and commercial health plans.

Pennell says that although it costs more to pay for a NGS test than a single-gene EGFR test, it is less expensive to pay for a single NGS test than multiple gene panel tests covering 

 mutations. Ordering 1 NGS test is more cost effective than multiple separate single-gene tests, and it covers all the same genes, and potentially more.

Nathan A. Pennell, MD, PhD, director, Lung Cancer Medical Oncology Program, Cleveland Clinic Taussig Cancer Institute, discusses the cost-effectiveness of next-generation sequencing for patients with metastatic non–small cell lung cancer.

Nathan A. Pennell, MD, PhD