Balancing Novel Therapies and Equitable Access in NSCLC Treatment Pathways

In this interview, Estelamari Rodriguez, MD, MPH, University of Miami, discusses the challenges and advancements in non-small cell lung cancer (NSCLC) care, including strategies for managing uncommon EGFR mutations, the potential of antibody-drug conjugates, barriers to comprehensive molecular testing, and approaches to balancing cost-effective treatments with equitable patient access.

Please state your name, title, and any relevant clinical experience.

Estelamari Rodriguez, MD, MPH: I'm Dr Estelamari Rodriguez. I am the clinical research lead of thoracic oncology research at the Sylvester Comprehensive Cancer Center, University of Miami. I am also the associate director of community outreach for thoracic oncology at our cancer center and have 20 years of experience in thoracic oncology. My work includes phase I experimental therapeutics, and I exclusively see patients in clinic across the entire continuum of lung cancer—from early-stage, to advanced disease and survivorship.

Treating patients with non-small cell lung cancer (NSCLC) who have uncommon EGFR mutations presents a unique challenge. What is the latest strategy and therapeutic options for this subgroup, and how do they impact patient outcomes?

Dr Rodriguez: The term uncommon is interesting because these mutations are not as uncommon if you see a lot of patients with lung cancer. To date, we celebrate, in a way, when we see typical mutations because there are several drugs available in that space, including multiple generations of EGFR inhibitors, and those patients often do well for a couple of years. Even when they relapse, there are an increasing number of treatment options.

The uncommon mutations include many variants. I would categorize EGFR exon 20 insertion as one of the mutations we used to consider uncommon. However, with treatments such as amivantamab, these have become treatable EGFR mutations, offering patients meaningful benefits.

For other, rarer mutations such as EGFR G719A and others, there has been significant effort to develop better therapeutic targets that overcome resistance. Currently, data support the use of afatinib and osimertinib in this space, but we are really interested in seeing how this new class of agents, such as bispecific antibodies or antibody-drug conjugates, may provide targeted therapy while simultaneously offering the benefits of chemotherapy.

The uncommon mutation space will change. The most critical step is recognizing these mutations. While testing for EGFR mutations is improving overall, in some regions of the US and globally, people are testing for the common mutations alone and missing these other variants, or if they're there, they're not recognizing them because they are not flagged as actionable. However, I have treated patients with uncommon mutations who experienced significant benefits, even in cases involving brain metastases, from third-generation TKIs available on the market.

Antibody-drug conjugates (ADCs) are emerging in NSCLC treatment. Could you elaborate on their efficacy, associated adverse events, and management strategies?

Dr Rodriguez: The ADC currently approved for NSCLC is trastuzumab deruxtecan, which is indicated for HER2-positive lung cancer. Providers have a lot of experience with this drug in the breast cancer space, it has demonstrated efficacy as a targeted option, including activity in the CNS, and long-term effectiveness. Although initially approved based on the DESTINY trials as a second-line option, these drugs can work really well in the first-line setting as well. They offer patients activity in the brain, as observed in breast cancer, and can be highly targeted and effective.

With that, due to their chemotherapy-based payload, ADS have some special toxicities. We have seen pneumonitis, likely because of a bystander effect as the drug is spread out through the lungs. While this side effect can be managed, it differs from the pneumonitis seen with TKIs or radiation, being more specific to chemotherapy. We also have seen cytopenias and significant nausea in some patients. These drugs are also delivered via infusion, requiring patients to visit the cancer center more frequently, unlike oral targeted therapies, which allow for at-home management and are more conducive to survivorship and the overall treatment journey.

Another ADC that initially showed promise but has had mixed results is the TROP2 inhibitor class. Although, I will say that datopotamab deruxtecan already has an FDA breakthrough designation for EGFR osimartinib resistance. This provides an option for patients who have progressed through amivantamab or other EGFR-targeted agents. Clinical trials have demonstrated better responses with datopotamab deruxtecan compared with docetaxel, which remains the standard second-line therapy but offers limited duration of response and significant side effects. These drugs are going to be meaningful for these patients because they also have CNS activity. You don't need to find TROP2 expression, although there are some trials and ways to look for TROP2 patients, I think we'll be able to provide these options as an improvement for patients who have not benefited and had a lot of toxicity from docetaxel.

That said, the toxicities associated with TROP2 inhibitors are distinct, including mucositis and ocular toxicity. Again, these agents have been used in the breast cancer setting, where clinicians have learned to manage these toxicities with dose reductions and aggressive supportive care. At the beginning of the year, the expectation had been that TROP2 inhibitors would be an option for all patients who progress. However, based on their lack of demonstrated efficacy in improving overall survival compared with docetaxel limits their use. Instead, these agents are going to be reserved for the EGFR-positive patients who progress after standard treatments.

What are current barriers to widespread implementation of comprehensive molecular testing for NSCLC, and how can multidisciplinary care enhance testing rates and treatment selection?

Dr Rodriguez: We have made a lot of progress in recognizing that lung cancer is a disease that requires baseline testing. Timing and the amount of tissue samples are major challenges. Many patients present with advanced disease and are often very sick when they are hospitalized. They’re not going to have time to get the necessary molecular information to make a treatment decision.

Some patients are started on chemotherapy and immunotherapy without comprehensive molecular data, and they don't do as well. Even with liquid biopsies, which can provide results within 10 days, sometimes it can take a month for a patient who has symptoms to make it to a doctor's office and some of these tests aren’t performed in the hospital. Turnaround time remains a significant barrier.

Another issue arises with pulmonologists in the community, who may not consistently collect enough tissue for testing. Even when the pulmonologist does everything correctly, we meet with a patient and the tissue is at an outside hospital that doesn't have the resources to send them promptly. It can take another 3 weeks for to retrieve the tissue to then wait another 2 to 3 weeks for the results. You're now talking about a 6-week turnaround time, which is unacceptable, particularly for young patients or those with significant lung cancer symptoms.

There is also a lot of variability in terms of insurance coverage, many hospitals don't do reflex testing because they don't want to be stuck with the bill. Patients often have a lot of reservations about doing concurrent liquid and tissue biopsy for the same reason. There is a critical need to standardize baseline testing for all patients.

Last month, we received an approval for NRG1 fusions, which account for less than 1% of lung cancer. Identifying this fusion is difficult because it requires an RNA-based platform, which not all institutions used. Awareness is also important—rare mutations may still provide actionable treatment options. The recent era of tumor-agnostic drug approvals has opened the door for us to do broad molecular testing for almost every patient with advanced cancer. These approvals allow us to find mutations that may be treatable with therapies initially approved for other indications.

In lung cancer, we now have several examples, including BRAF mutations, NRG1 fusions, even HER2 mutations, and even HER2 low approvals, which are also an approval for lung cancer, that are tumor-agnostic. This era of testing is not only a lung problem, it applies across advanced tumor types. You need tissue to be able to offer patients all of the options that these medications can give.

How do you balance the incorporation of novel and often expensive treatments within NSCLC clinical pathways while ensuring cost-effectiveness and equitable patient access?

Dr Rodriguez: I practice in the US but collaborate a lot with our partners in Latin America, and they can only access new treatments through clinical trials. It's completely the opposite in the US where, in a cancer center like ours, we struggle to get 10% to 15% of patients in clinical trials, partly because approved drugs are already available for purchase.

Even in the US, there are challenges with preapprovals and prior authorizations, especially when you have multiple drugs available, and figuring out the most cost-effective drug becomes necessary. How do you balance that? With education and information, patients can advocate for themselves with insurance companies about drugs that will benefit them with less toxicity, even if they are more expensive. For example, docetaxel, a second line therapy is not cheap and it's not free of toxicity. Delivering a first-line option that offers better long-term disease control can help avoid complications like brain metastases, hospital admissions, and the associated burden on patients and their families.

We fight for patients by advocating, writing letters, and participating in peer-to-peer approval calls. We do have guidelines in the US, such as those from the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO), that guide doctors in the community about what is considered standard care. That gives us a lot of information that we can go to insurance companies with. If a treatment is within these guidelines and an insurance company denies it, they have to justify their decision.

Sometimes I struggle with treatment pathways that exclude drugs known to cause toxicity in elderly patients but are necessary for younger patients. Sometimes when you're trying to get them to younger patients, you have to get on the phone and it's very burdensome for both the patients and providers, but it's critical to ensure patients receive the best care.

I do think that as more generic drugs come into the market, this issue will become even more relevant. Eventually, we'll have generic immunotherapy. That's coming. If it comes to the market at a lower cost, it could spark discussions about differences between immunotherapy agents. Some less expensive immunotherapy options are available, but their benefits appear marginal. From an insurance company perspective, however, there could be a big benefit in terms of cost reduction for the whole system.

Ironically, we probably spend more time fighting to get a $300 CT scan approved than a $10 000 drug. That said, these issues are all important to patients. In the US, if patients have insurance, we have a lot of options. However, for patients with Medicaid or those who are uninsured, it can be a struggle. Although, I will say that in the US, even US citizens who are uninsured often have access to compassionate programs that are very generous. In all the years I have practiced as a thoracic oncologist, if the patient is a US citizen who has a mutation, for example, we've been able to get that drug them.

There is going to be a little bit of a change in the next year. Medicare will implement a $2000 cap on annual out-of-pocket costs, which will create more equity between high and low earners. Currently, younger patients who are not Medicare-eligible often struggle with copays and rely on employer-sponsored insurance. In the Medicare space, there has been inequity in terms of copays, and I think it's going to become more equal. However, $2000 remains a significant burden for patients living in Social Security, especially in today’s economy. I think a lot of patient assistance programs are going to face challenges because there is an expectation that $2000 is a reasonable cost for all patients—when, for many, it’s not.

There is a lot to come, but I do think that there needs to be a balance. Patients are living better and longer lives, and there are more survivors of lung cancer today than when I began practicing as a thoracic oncologist. Like with breast cancer, they're going to advocate for all these drugs, even highly expensive drugs, to be covered because patients’ lives are at stake. There has been a lot of stigma around lung cancer that has really hurt these conversations between advocates and insurance companies, but I think that's changing.