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PER® Winter Lung Cancer Conference

Higher cancer death rates, less frequency of cancer screening, and increased rates of advanced cancer diagnoses in select demographics are a fraction of the health disparities occurring throughout oncology—and the lung cancer space is no exception, explains Gilberto Lopes, MD.

Specifically, in lung cancer treatment, the advent of immunotherapy and targeted approaches do not necessarily carry over to patients of low socioeconomic status and/or of developing countries, as they may not have access to care, says Lopes, who is the medical director for International Programs at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine. Additionally, such patient groups have lower participation in clinical trials.

With relation to race, for example, African-American male and female patients in the United States have the highest incidence and death rates for both colorectal and lung cancers, according to data from the National Cancer Institute.

In Brazil, the most common cancers in men, in descending order, are those of the prostate, lungs and airway, colon and rectum, stomach, and oral cavity.

 In females of Brazil, the most common cancers are those of the breast, colon and rectum, cervix, lungs and airway, and thyroid. Additionally, in Brazil, although there was a reported decline in lung cancer mortality among men in the state capitals in 2015, there was an increase in smaller cities.

However, solutions are forming to bridge the disparity gaps and differences in care, Lopes says.

Your talk at this meeting is focusing on global oncology and lung cancer, specifically on disparities and solutions. What are some of the disparities we have observed in recent years? Has anything really changed?

What are the causes for some of the disparities in treatment? What demographics have a more difficult time getting treatment?

What solutions do we have to bridge these gaps?

Are these disparities specific to lung cancer, or do you find that this happens across tumor types?

What are the key messages that you hope the community oncologists in attendance take home from your presentation?

 prior to the 5th Annual Miami Lung Cancer Conference on March 10, 2018, Lopes shed light on the global disparities occurring in lung cancer care and some of the steps that are being taken to better serve patients with the available and emerging therapeutic approaches.

 With the advent of molecularly targeted agents and immunotherapy, which have improved survival and quality of life for certain lung cancers but come with an increased cost, there are growing differences in the way patients who have no insurance or who are treated in low-resource settings do when compared with those treated in academic centers in the United States. In countries outside of North America and Western Europe, access is an even greater issue and a small minority of patients receive targeted agents and immunotherapy.   

Most importantly, lack of insurance adversely affects patients, but minority patients in the United States also have lower access to care and molecular testing and have much lower rates of participation in clinical trials. Moreover, patients in rural areas also struggle with access to healthcare systems and Medicaid patients tend to do worse than patients who have Medicare or private health insurance. Finally, patients with larger copays for intravenous or oral medications are less compliant and, therefore, also have worse outcomes.  

In low-resource settings, we need to increase access to health care, smoking cessation, screening low-dose CT scans, surgery, chemotherapy, radiation, molecular testing and targeted therapy, immunotherapies and clinical trials are of paramount importance to bridge these gaps. At Sylvester Comprehensive Cancer Center at the University of Miami, we are working on a number of initiatives to strengthen cancer registries, prevention and treatment networks in Latin America and the Caribbean. In the United States, we need to make sure that all patients have access to healthcare. A diverse workforce will also go a long way to help improve care for patients who come from minority groups.

Many of the disparities I mentioned are shared across the cancer spectrum and policies designed to address them would be far-reaching. Lack of access to molecular testing and immunotherapies, however, affects patients with lung cancer more than it might affect patients with other types of malignancies.  

That with increasing costs, patients often can’t bear their copays and it is important that health systems take that into consideration when treating patients.

National Cancer Institute. Cancer health disparities. Published March 11, 2008. cancer.gov/about-nci/organization/crchd/cancer-health-disparities-fact-sheet. Accessed March 7, 2018.

de Souza JA, Hunt B, Asirwa FC, Adebamowo C, Lopes G. Global health equity: cancer care outcome disparities in high-, middle-, and low-income countries.

2016;34(1):6-13. doi: 10.1200/JCO.2015.62.2860.

Gilberto Lopes, MD, discusses the global disparities occurring in lung cancer care and some of the steps that are being taken to better serve patients with the available and emerging therapeutic approaches.

Expert Addresses Global Disparities in Lung Cancer, Efforts to Bridge the Gap

Experts are looking to push immunotherapy even further in the treatment landscape of lung cancer over the next few years by exploring checkpoint inhibitors in early-stage and locally advanced disease, testing immune-based therapies in small cell lung cancer (SCLC) and mesothelioma, and tweaking some of the current methods to avoid resistance.

The 5th Annual Miami Lung Cancer Conference, taking place on March 10, 2018, will cover this expanding use of immunotherapy, as well as other treatment advances in lung cancer. The conference will also include a session on head and neck cancer.

“This jam-packed, condensed day is an opportunity to get the highlights and be able to ask detailed questions during the [Medical Crossfire

 component],” said Julie R. Brahmer, MD, co-chair of the meeting. “A benefit of these Medical Crossfires is asking provocative questions.”

 Can you provide an overview of the immunotherapy session that you are moderating?

ahead of the meeting, Brahmer, an associate professor of oncology, co-director of the Upper Aerodigestive Department, Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Medicine, shared her most anticipated topics, including first-line immunotherapy, targeted therapies for molecularly driven tumors, and recently released guidelines for the treatment of patients with lung cancer.

 The first few hours [of the conference] will be discussing cutting-edge therapies. Dr Justin Gainor of Massachusetts General Hospital will be discussing the NCCN guidelines on the use of nivolumab (Opdivo) plus ipilimumab (Yervoy) for SCLC, as well as trials of immunotherapy in mesothelioma. With the rapidly changing treatment landscape, there are certainly a lot of questions and patient cases to discuss. There will also be a very timely discussion about maintaining patients on immunotherapy and immune-related toxicities. While rare, these side effects do have to be managed differently than the typical side effects that we see with chemotherapy. Discussing the current guidelines for the treatment of toxicities will be interesting. Recently, ASCO and NCCN have come out with guidelines that now help us treat patients who develop side effects.

What is the take-home message on your presentation on first-line immunotherapy and avoiding resistance?

You are also moderating the Mutation-Independent Therapy session. What are you looking forward to discussing in that panel?

As co-chair, what other news coming out of the meeting are you particularly excited to hear about?

We will also be discussing therapies for patients with mutation-based lung cancer. Folks will be very excited to attend this cutting-edge seminar discussing the rapidly changing treatment landscape. Now we have multiple inhibitors for patients with 

 mutations, as well as new approaches for patients with 

V600E lung cancer. We have been introduced to this subset of non—small cell lung cancer (NSCLC) in the past year. We are very excited to have some of the physicians who are on the forefront of changing treatments for NSCLC, SCLC, and mesothelioma. I look forward to listening to these exciting talks. 

Be aware that the treatment landscape is changing rapidly, and we need to assess for PD-L1 status early in order to treat patients with squamous cell histology with first-line immunotherapy, such as pembrolizumab (Keytruda). For nonsquamous cell histology, if PD-L1 is expressed, single-agent pembrolizumab is an option. Pembrolizumab plus chemotherapy is an option for those without a known PD-L1 status. We will be discussing the news release that showed that the larger phase III study in nonsquamous cell histologies combining pembrolizumab with pemetrexed and carboplatin does improve overall survival and progression-free survival.

I am looking forward to discussing the general management of these patients, as well as how we think that the future landscape is going to play out. Certainly, we will touch on how antiangiogenic therapies are here to stay, as they help us both with mutation therapy and mutation-independent therapy. Dr Gilberto Lopes of the University of Miami Sylvester Comprehensive Cancer Center will be discussing global oncology and disparities in lung cancer, which will certainty be a great talk.

I am trying to keep my hand on the pulse of head and neck cancer treatment, so that session will be exciting. Also, there are parts of our practice that do remain controversial, and although you do have to treat on a patient-by-patient basis, it is good to get a feel of how physicians handle different questions in the clinic. These answers can be helpful to take back into your own clinic.

Julie R. Brahmer, MD, discusses first-line immunotherapy, targeted therapies for molecularly driven tumors, and recently released guidelines for the treatment of patients with lung cancer.

Brahmer Highlights Latest on Immunotherapy and Other Lung Cancer Advances

Sarah B. Goldberg, MD, MPH, an assistant professor of medicine at the Yale School of Medicine and Yale Cancer Center, discusses testing for and treating resistance to EGFR tyrosine kinase inhibitor (TKI) therapy in non—small cell lung cancer (NSCLC).

In December 2017, the FDA granted a priority review designation to a supplemental new drug application for the use of osimertinib (Tagrisso) as a first-line treatment for patients with NSCLC whose tumors harbor 

 mutations (exon 19 deletions or exon 21 [L858R] substitution mutations). Osimertinib is now being used both on and off trial, which has cause a shift in the testing and treatment landscape of NSCLC, says Goldberg. Although investigators do not fully understand resistance after osimertinib, Goldberg suggests that it may be different after use as first- and second-line treatment.

Goldberg says that many clinicians are using both liquid and tissue biopsies to test their patients for mutations. The debate between liquid and tissue biopsy is continually evolving, and while a liquid biopsy is more comfortable for the patient, it can sometimes provide limited information, says Goldberg.

Sarah B. Goldberg, MD, MPH, an assistant professor of medicine at the Yale School of Medicine and Yale Cancer Center, discusses testing for and treating resistance to EGFR tyrosine kinase inhibitor (TKI) therapy in non–small cell lung cancer. 

Dr. Goldberg Discusses Resistance to EGFR TKI Therapy in NSCLC

In September 2017, the NCCN updated its clinical practice guidelines to include frontline osimertinib (Tagrisso) for the treatment of patients with locally-advanced or metastatic 

-positive non—small cell lung cancer (NSCLC).

Although osimertinib is still only approved by the FDA in the second-line (the frontline decision date is pending), physicians are already excited about using the treatment in the frontline setting, according to Sarah B. Goldberg, MD. She adds that upfront use of osimertinib is prompting questions related to testing, sequencing, and resistance.

“This is still something that is constantly evolving, and we are still learning about the best ways to understand resistance and manage patients,” Goldberg explains.

 You are giving a presentation on resistance to EGFR TKI therapy. How has this topic evolved in just over the last year?

 ahead of the 5th Annual Miami Lung Cancer Conference, Goldberg, an assistant professor of medicine at the Yale School of Medicine and Yale Cancer Center, discussed the key points of her lecture on testing for and treating resistance to EGFR TKI therapy in NSCLC.

 There have been a lot of changes in testing for and treating EGFR TKI resistance in the last year. Many of these changes are because we are now starting to treat with osimertinib in the first-line setting, both on trial and off trial. As we start to do that, we see different mechanisms of resistance come up after first-line osimertinib, and that leads to different ways of thinking on how to overcome resistance. Also, as we are sequencing the EGFR inhibitors using first- or second-generation inhibitors first and then using osimertinib; we are learning more about mechanisms of resistance after second-line osimertinib. We are also trying to better understand how to overcome resistance there. What we are starting to understand is that resistance after osimertinib may be different after first- and second-line treatment. That has become such an important area of research.

The lung cancer community is anticipating the FDA’s decision to approve osimertinib in the frontline setting. What are your thoughts on how this potential approval could impact the landscape?

In terms of how to test for it, this is something that started several years ago. Whether to get a liquid biopsy or a tissue biopsy is still an evolving question. Many of us are doing both, and while a liquid biopsy is much easier for patients, it can sometimes limit the information that you get.

We saw that the FLAURA trial, which compared first-line osimertinib versus either erlotinib (Tarceva) or gefitinib (Iressa), demonstrated a significant benefit in terms of response rate and progression-free survival (PFS) for osimertinib. Based on those results, there has been a lot of enthusiasm to use osimertinib in the first-line setting. It has become a part of the NCCN guidelines, which a lot of people look to for guiding treatment. Technically it is not yet an approved therapy in the first-line setting. An FDA approval gives oncologists a stronger backing to use a drug, and it becomes easier for patients to get through insurance. It will lead to more people using it as a first-line treatment. 

If osimertinib is approved in the first-line setting, will we face sequencing challenges? If we treat with osimertinib upfront, what could you give as a second-line treatment?

It will also be useful to see more data from FLAURA, specifically the overall survival (OS) data. We had some of that information in the initial presentation and paper from the FLAURA trial, but the data for OS were still immature. Over the next few months, that data will be more important. The FDA approval is important, but so are the trial data. 

We learned from the FLAURA trial that using frontline osimertinib does improve PFS compared with using a first-generation EGFR TKI. If you use the first-generation EGFR TKI first, you can use osimertinib second in about half of the patients who will develop T790M. You can use osimertinib in the first-line setting, but what do you do in the second-line setting? That is the potential sequencing challenge. 

Currently, we do not have an option that has been proven to be effective as a second-line targeted therapy after osimertinib. There have been some emerging data that show, depending on the mechanism of resistance, that there may be options in the targeted therapy realm after osimertinib.

For example, if a secondary mutation arises in 

called C797S, a first-generation EGFR TKI could potentially be effective after osimertinib. The data for that are just emerging, but it has not been thoroughly investigated. It is something that could be considered as an option, but it has not been studied in a prospective trial. After osimertinib, a standard treatment is probably chemotherapy, and a consideration could be given to immunotherapy as well, which is a whole separate discussion. After osimertinib, it involves thinking about other options besides targeted therapies.

What other resistance mechanisms occur after first-line EGFR-targeted therapy other than T790M?

There are other mechanisms of resistance that arise after osimertinib, and some of those may be able to be targeted, but that is in the realm of clinical trials. That is a great option for patients to consider after osimertinib in the first-line setting. There is a lot to learn and there are some exciting opportunities there, but again, looking at things such as 

 amplification is all in the clinical trial realm. There are a lot of questions on sequencing after osimertinib. If the PFS is so far superior to a first-generation TKI, then it is important what you do second. However, if you think about OS, it might not matter what you do second because you get a much longer benefit with 1 drug over the other.

T790M occurs in about half of patients who progress after treatment with first- or second-generation EGFR inhibitors. What about the other half? There are some patients who will develop 

amplification. It is a fairly small number of patients at approximately 5%. However, I believe this is a very important subset of patients because there are now trials with MET inhibitors that are looking exciting in them. It is not yet an approved therapy for the 

-amplified population, but it is something to keep an eye on and, if there is a trial available, it could be a great option for patients. 

There are other patients who will develop a small cell transformation after treatment with EGFR inhibitors. Again, this is a fairly small subset of patients, but it is an important one to consider because those patients tend to act like a typical patient with small cell lung cancer (SCLC) in that their tumor can progress very rapidly—and also in that they can respond very well to small cell—directed therapy, which is typically chemotherapy with a platinum-based agent and etoposide. That is something to be aware of, and an important reason to think about doing a tumor biopsy and not just a liquid biopsy; you need to be able to do a histologic diagnosis for SCLC. It is a small number of patients, but I have seen it several times so it is something that we need to keep in mind, especially for those patients who are having more rapid progression on EGFR-directed therapies. 

Liquid biopsies are being used more frequently in lung cancer. What is your approach on when to perform a plasma-based biopsy versus standard tissue?

There are other alterations that we see as well, such as 

 amplification. What to do about those alterations is unknown, but these are all areas of ongoing research. 

Biopsies are really important in understanding the mechanism of resistance. Fortunately, now we have 2 options. We can get a tissue biopsy, which has been the standard forever, but now we are able to get a liquid biopsy, which is a blood test looking for circulating tumor DNA. Compared with an invasive biopsy, liquid biopsy is much easier for patients, and it often can provide all of the information that we need to treat the patient. It can give the information on the mechanism of resistance—T790M presence or not&mdash;and other things that are present in the tumor. 

The issue with a liquid biopsy is that it does have a false-negative rate. In the studies looking at progression on a first- or second-generation EGFR inhibitor, the false-negative rate was around 30%—so it missed T790M about 30% of the time. That is a big number. What that tells me is that if you do a liquid biopsy as your first step, and it is negative for T790M, you should really consider doing a tissue biopsy because you do not want to miss those patients who have T790M, as they could receive osimertinib as a second-line treatment. 

A liquid biopsy could be considered as a first option for biopsy, followed by a tissue biopsy. The alternative is that you could do a tissue biopsy and if it gives you the information that you need, then that is the end of it. In some ways, you could think of liquid biopsy as sampling multiple sites of resistance. It is not just getting 1 site of resistance, it’s looking at all sites at once. It has become a part of standard treatment, with the knowledge that you may have to give a tissue biopsy. 

Can you discuss the FDA expanded approval of afatinib (Gilotrif) for rare 

You should also think about the issue of SCLC in patients. In patients who do have rapid progression or are declining quickly, I would still consider getting a tissue biopsy as my first step because I want to make sure I am not missing SCLC. I think of tissue biopsy and liquid biopsy as complementary; I use them both in different ways and occasionally do both if I do not want to miss something in a rapidly evolving clinical scenario. They both have benefits and can both be used to analyze the mechanism of resistance in a patient. Utilizing these ensures that you are finding the right next option for the patient.

 mutations are considered uncommon. That is a subset of mutations lumped together because they aren't the common exon 19 mutations or L858R point mutations. Those mutations are very heterogeneous; some of them are mutations that are sensitized to EGFR inhibitors and some are resistant. There was a recent retrospective study looking at several trials with afatinib, and those trials included some of these uncommon mutations. Investigators were able to see the efficacy of afatinib in those mutations; some of these point mutations were sensitizing to afatinib. That led to an approval for afatinib in several of those mutations.

The mutations that afatinib was not effective in were the ones that we have known about for a long time—the T790M mutation and the exon 20 insertion mutations. Afatinib and first-generation drugs are not effective in those mutations.

Sarah B. Goldberg, MD, discusses testing for and treating resistance to EGFR TKI therapy in non-small cell lung cancer. 

PER® Winter Lung Cancer Conference | Conference

Expert Addresses Global Disparities in Lung Cancer, Efforts to Bridge the Gap

Brahmer Highlights Latest on Immunotherapy and Other Lung Cancer Advances

Dr. Goldberg Discusses Resistance to EGFR TKI Therapy in NSCLC

Goldberg Gives Expert Insight on EGFR-TKI Resistant NSCLC