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State of the Science Summit on Advanced NSCLC

Robert J. Cerfolio, MD, director of the Lung Cancer Center, chief of clinical thoracic surgery, NYU Langone’s Perlmutter Cancer Center, discusses the role of surgery in lung cancer.

Despite therapeutic advances, surgery has retained its role in the treatment of patients with lung cancer, explains Cerfolio. However, the rate of benign resection has decreased tremendously. Now, the benign resection rate is approximately 5%, whereas it used to range from about 10% to 12%. If anything, surgeons are able to be more selective with surgery because they are now able to more effectively diagnose a patient’s condition in a more minimally invasively way.

However, physicians have just scratched the surface in their understanding of how cancer works, adds Cerfolio. Every day physicians are finding different receptors on cancer cells and other cells and shields. For example, physicians know that PD-L1 protects normal cells and also is on cancer cells. As more research is done, physicians are learning more about how it can get into these cells. With regard to surgery, minimally invasive techniques are going to change practice. It is only a matter of time before surgeons are going to go down through the mouth or the nose to treat lung cancer, concludes Cerfolio.

Dr. Cerfolio on the Role of Surgery in Lung Cancer

Elaine Shum, MD, medical oncologist, NYU Langone’s Perlmutter Cancer Center, discusses mechanisms of resistance in patients with oncogene-driven non—small cell lung cancer (NSCLC).

Based on data from the phase III FLAURA and ALEX studies, osimertinib (Tagrisso) and alectinib (Alecensa) have become the recommended frontline treatments for patients with 

-positive NSCLC, respectively. Physicians are still learning why tumors develop mechanisms of resistance, says Shum. Although there is no substantial insight into why this occurs, there is reason to believe that these targeted agents isolate a clone and allow for another clone to drive the disease undetected. Future studies involving more biopsies at the time of progression will hopefully shed more light on this issue, she adds.

For patients who have developed resistance to treatment, combination therapy with various TKIs may be a potential strategy, says Shum, although toxicity may become an issue. Additionally, some anecdotal studies have shown improved outcomes with an EGFR inhibitor and MET inhibitor in 

Elaine Shum, MD, medical oncologist, NYU Langone’s Perlmutter Cancer Center, discusses mechanisms of resistance in patients with oncogene-driven non–small cell lung cancer (NSCLC).

Dr. Shum on Mechanisms of Resistance in Oncogene-Driven NSCLC

Joshua K. Sabari, MD, assistant professor of medicine, NYU Langone's Perlmutter Cancer Center, discusses the role of immunotherapy in the treatment of patients with small cell lung cancer (SCLC).

SCLC is a difficult disease, Sabari says. Frontline chemotherapy seems to work very well, with response rates in the order of 70% to 80%. Unfortunately, all patients will eventually relapse with chemotherapy-refractory disease. Until the past year, no changes had been made beyond that setting in over 2 decades.

The first drug approval in over 20 years came in August 2018, when single-agent nivolumab (Opdivo) was granted an accelerated FDA approval for the treatment of patients with SCLC with disease progression following platinum-based chemotherapy and 1 other line of therapy. Objective response rates were low, at approximately 10%, Sabari notes, but the checkpoint inhibitor was still approved.

Additionally, atezolizumab (Tecentriq) in combination with platinum-based therapy and etoposide could also become the standard of care in the frontline setting, based on data from the IMpower133 study. Results of this trial demonstrated an estimated 2.0-month improvement in overall survival for the atezolizumab arm. Although this is modest, it is a major advance for the field, Sabari explains. Additional immunotherapy combinations could be a part of future SCLC management.

Joshua K. Sabari, MD, assistant professor of medicine, NYU Langone's Perlmutter Cancer Center, discusses the role of immunotherapy in the treatment of patients with small cell lung cancer.

Dr. Sabari Discusses Role of Immunotherapy in SCLC

Kwok-Kin Wong, MD, PhD, Anne Murnick Cogan and David H. Cogan Professor of Oncology, Department of Medicine, and director of the Division of Hematology and Medical Oncology at NYU Langone’s Perlmutter Cancer Center, discusses the current landscape of non—small cell lung cancer (NSCLC).

NSCLC is a very heterogeneous disease that can be divided by oncogenic-driven lung cancer and nononcogenic-driven lung cancer, explains Wong. For patients with oncogene-driven lung cancer, there have been several FDA approvals for patients with 

 mutations as well as encouraging single-agent activity for patients with 

For patients without a targetable mutation, immunotherapy has made a significant impact on care. With these agents, physicians are observing durable responses of up to 7 years in select patients—–even cures in some cases; unfortunately, this impact has only been seen in a small subset of patients. Efforts are ongoing to design clinical trials that will extend duration of response to the majority of patients with lung cancer whose benefits only measure about 12 to 18 months with immunotherapy.

Kwok-Kin Wong, MD, PhD, Anne Murnick Cogan and David H. Cogan Professor of Oncology, Department of Medicine, and director of the Division of Hematology and Medical Oncology at NYU Langone’s Perlmutter Cancer Center, discusses the current landscape of non–small cell lung cancer (NSCLC).

Dr. Wong on the Current Landscape of NSCLC

Single-agent immunotherapy, targeted therapies, and combinations of the 2 are demonstrating durable responses of up to 7 years in subsets of patients with advanced non—small cell lung cancer (NSCLC), giving physicians hope that the benefit can be extended to a greater proportion of patients, said Kwok-Kin Wong, MD, PhD.

“It is an amazing time to think about the combinations of drugs we can put together to increase the number of patients who respond to either targeted therapy or immunotherapy,” said Wong, Anne Murnick Cogan and David H. Cogan Professor of Oncology, Department of Medicine, and director of the Division of Hematology and Medical Oncology at NYU Langone’s Perlmutter Cancer Center. “Immunotherapy has come to the forefront of the treatment of lung cancer patients.”

Clinical trials continue to push the needle forward and have proven essential for patients with nononcogene-driven and oncogene-driven disease. For example, the combination of atezolizumab (Tecentriq) with bevacizumab (Avastin), carboplatin, and paclitaxel (BCP) resulted in a 22% reduction in the risk of death versus BCP alone as frontline treatment for patients with metastatic disease. Results reported from the phase III IMpower150 trial led to the FDA approval of this regimen in December 2018.

Moreover, next-generation TKIs continue to emerge for both 

-positive lung cancer treatment. In April 2018, the third-generation TKI osimertinib (Tagrisso) was approved by the FDA for patients with EGFR-mutated NSCLC based on the results from the phase III FLAURA trial. Later that year, the results from the phase II B7461001 trial were released, which led to lorlatinib’s (Lorbrena) second-line approval for patients with 

: What are some exciting data we have seen to date in lung cancer? 

 State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Wong discussed updates in NSCLC and the importance of enrolling patients in clinical trials to further progress the field.

: NSCLC is a very heterogeneous disease. We can divide it into cancers that have known oncogenic drivers and cancers in which there are no oncogenic drivers. Incredible advances have been made on both sides. For oncogene-driven lung cancer, we are developing new drugs and more of those drugs are getting FDA approval.

For nononcogene-driven lung cancer or oncogene-driven lung cancer for which we do not have available therapies, immunotherapy has had an incredible impact on the treatment of these patients. We are extending the survival of these patients by months, if not years.

In a very small subset of patients with advanced lung cancer, we are seeing cures or durable response rates for up to 7 years. It is something I never thought would happen in my lifetime. When you start going that far out, you can start to think about the potential for cure. Unfortunately, that is a very small subset of patients.

At this point, which patients do you recommend to go on a clinical trial?

Has lung cancer become a chronic disease similar to some other cancers?

There are many interesting ongoing clinical trials that are trying to extend the duration of response for the majority of patients whose benefits only measure about 12 to 18 months with immunotherapy.

A patient who has exhausted all standard treatments would benefit from clinical trials. This is the only way we can objectively measure how a novel drug that has not been FDA approved [performs] and whether it works better than the standard of care. We can learn quite a bit about the patient's cancer, as well as the biology behind the cancer with clinical trials. Clinical trials have now become so sophisticated that we can learn about that particular patient's disease and extend that knowledge to other patients.

We're getting there, but we are not quite there yet. We talk about the tail in the overall survival [curve]. There are patients who have extended survival up to 7 years. For those patients, that is a chronic disease. Again, that is a small subpopulation of patients. We want to expand that population.

[The prognosis] has completely changed the way we look at lung cancer. When a patient with advanced lung cancer came in 7 years ago, we told them the prognosis was about 12 to 18 months. Now, we can honestly say that we do not know. We have patients with advanced lung cancer who are 5 to 7 years out with no known oncogenic drivers.

With oncogene-driven lung cancer, we have made incredible progress. We have second-generation targeted therapies. For a subset of those patients, we are turning the cancer into a chronic disease. You have to divide patients into those with known oncogenic drivers for which there are targeted therapies, those with no known oncogenic drivers, or those with oncogene-driven lung cancer for which we do not have drugs yet.

Socinski MA, Jotte R, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized ph 3 study of atezolizumab (atezo) chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. 

Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. 

 2018; 378:2288-2301. doi: 10.1056/NEJMoa1716948.

Kwok-Kin Wong, MD, PhD, discusses updates in non–small cell lung cancer and the importance of enrolling patients in clinical trials to further progress the field.

Treatment Breakthroughs Advance Care Across Heterogeneous NSCLC Population

Joshua K. Sabari, MD, assistant professor of medicine, NYU Langone's Perlmutter Cancer Center, discusses biomarkers of immunotherapy response in patients with non—small cell lung cancer (NSCLC).

The reliability of PD-L1 expression as a biomarker is up for debate in the field, but Sabari says he still orders PD-L1 testing for his patients and uses the 50% cutoff to define if a patient should receive pembrolizumab (Keytruda) alone or in combination with chemotherapy. He adds that he does this for patients presenting with non—small cell adenocarcinoma as well as those with squamous NSCLC.

Sabari notes that if you parse the data, no matter how you look at it, patients with high levels of PD-L1 expression have a greater chance to benefit from immunotherapy. His treatment approach is to weigh the risks of each therapy with the benefits. For example, if a patient has a PD-L1 expression of 100%, who he knows has a high likelihood of responding to immunotherapy, then chemotherapy can be avoided.

Another key biomarker coming down the pike is tumor mutational burden (TMB), he adds. Although this is a controversial topic, there are studies looking at it prospectively as well as retrospectively. For example, the CheckMate-227 trial, which was recently published, showed an improvement in patients who had high TMB. The controversy, he explains, lies in the question of how to define “TMB-high” and if it is possible to establish a unified definition by looking at different assays.

Joshua K. Sabari, MD, assistant professor of medicine, NYU Langone's Perlmutter Cancer Center, discusses biomarkers of immunotherapy response in non–small cell lung cancer.

Dr. Sabari Discusses Immunotherapy Biomarkers in NSCLC

Following frontline TKI approvals, researchers are still trying to determine the role of older-generation TKIs in the treatment of patients with oncogene-driven non—small cell lung cancer (NSCLC), as well as ways to overcome acquired resistance to these agents, said Elaine Shum, MD.

Osimertinib (Tagrisso), a third-generation EGFR TKI, gained FDA approval in the frontline setting in April 2018 for patients with NSCLC whose tumors harbor 

 mutations (exon 19 deletions or exon 21 L858R substitution mutations). The decision was based on data from the phase III FLAURA study, in which frontline osimertinib reduced the risk of progression or death by 54% versus first-generation TKIs erlotinib (Tarceva) or gefitinib (Iressa). The median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 15.2-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; 

 <.0001). Overall survival (OS) data have not yet been published.

-positive NSCLC treatment, alectinib (Alecensa) has been identified as standard frontline therapy following its November 2017 FDA approval. In November 2018, lorlatinib (Lorbrena) became the most recent ALK inhibitor to be approved for second-line treatment following progression on 1 or more ALK TKIs.

: What are the updates in frontline options for patients with oncogene-driven NSCLC?

 State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Shum, a medical oncologist at NYU Langone’s Perlmutter Cancer Center, discussed the rapidly evolving treatment options for patients with oncogene-driven NSCLC.

: It has been a very exciting past couple of years in terms of new FDA approvals for drugs in the frontline setting. In my presentation [at the State of the Science SummitTM], I focused on ALK- and EGFR-[targeted therapies], and I also touched on some of the rarer oncogenic drivers.

-mutated NSCLC, osimertinib is approved in the frontline setting. What are some unanswered questions with this drug?

What are your thoughts on the use of dacomitinib (Vizimpro) in the 

In what patients would you use an earlier-generation TKI? 

What are some ways to overcome resistance to these therapies? 

How important is next-generation sequencing (NGS) testing?

What are other emerging biomarkers in NSCLC?

, specifically, have seen some significant additions to the landscape. For example, I discussed the FLAURA data, which everyone has become familiar with. In the 

 space, the 19th Annual World Conference on Lung Cancer showed us some big data with brigatinib (Alunbrig); it is important to understand how this affects alectinib. In 

-driven disease, we still have our trusted agent crizotinib (Xalkori).

The data from FLAURA were very impressive and led to the FDA approval in the frontline setting. We are definitely already using this in practice. One thing we still don't have are OS data; however, we saw a significant PFS benefit with this drug, so I don't think any surprising OS data are going to change the way we use osimertinib. The effect on central nervous system penetration we are seeing with osimertinib is really what takes it beyond the other EGFR inhibitors.

Dacomitinib had very impressive data in the ARCHER 1050 study, but the toxicity profile gives us reason for concern. There is much stronger toxicity than what we are used to seeing with EGFR TKIs, especially with osimertinib being a generally well-tolerated drug. For me, personally, I don't think I'll be using dacomitinib simply based on the toxicity. However, as we learn more about sequencing these EGFR TKIs, dacomitinib could have a role. In other parts of the world, dacomitinib could be the right choice.

Based on the ALEX study, alectinib should be what we use in that setting. Brigatinib has certainly been an effective drug, but we obviously don't have a head-to-head comparison between the 2 agents. For now, alectinib would be my choice.

[I would use these agents] in patients with uncommon 

. These mutations are found in a very small percentage of patients, but they are there. For these patients, I wouldn't be rushing to use osimertinib upfront. Afatinib (Gilotrif) has been approved for use in these uncommon patient populations.

It is a very good question, and we are still learning why tumors develop mechanisms of resistance. We don't know enough yet about why this happens, but it seems that the targeted agents we're using select out a clone and allow another clone to drive the disease and go undetected. More studies involving more biopsies at the time of progression can help us answer this. There is potential for us to use different TKIs in combination but toxicity becomes a concern. There are some anecdotal studies of 

 amplification, and they had improved outcomes with an EGFR inhibitor and MET inhibitor.

It is pretty obvious that every patient at diagnosis, especially with stage IV disease, should undergo NGS testing. We are finding new oncogenic drivers based on these NGS tests and it is helping us gear treatment in a more personalized way. As NGS becomes more accessible and affordable, it will become the standard and help us improve patient outcomes.

It is important for us to understand the much less common, but definitely present, oncogenic drivers, such as 

. These drivers appear in around 1% to 2% of patients with NSCLC but identifying them can make a difference for your patients because there are options available. Tumor mutational burden also seems to be an effective biomarker in terms of immunotherapy response.

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. In: Proceedings from the 2017 ESMO Congress; September 9-12, 2017; Madrid, Spain. Abstract LBA2_PR. oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/Osimertinib-vs-standard-of-care-SoC-EGFR-TKI-as-first-line-therapy-in-patients-pts-with-EGFRm-advanced-NSCLC-FLAURA.

Elaine Shum, MD, discusses the rapidly evolving treatment options for patients with oncogene-driven non–small cell lung cancer.

Shum Sheds Light on Oncogene-Driven NSCLC Treatment Options

The lung cancer landscape continued to shift dramatically in 2018. Immunotherapy continued to dominate the clinical trial space, next-generation sequencing (NGS) is now regularly used in practice, and liquid biopsies began to be more widely adopted.

One of the pivotal decisions in 2018 was the FDA approval of durvalumab (Imfinzi) for the treatment of patients with locally advanced, unresectable stage III non—small cell lung cancer (NSCLC) who have not progressed following chemoradiotherapy. The decision was based on data from the PACIFIC trial, in which consolidation immunotherapy with durvalumab significantly improved progression-free survival and overall survival (OS) in patients with stage III NSCLC.

: What data have been most impactful in lung cancer over the past year? 

 State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Joshua K. Sabari, MD, assistant professor, Department of Medicine, (NYU Langone’s Perlmutter Cancer Center, reflected on the rapidly advancing landscape of lung cancer.

: In the early-stage setting is the PACIFIC trial, which looked at durvalumab after patients received concurrent chemotherapy and radiation. The results of that study were groundbreaking leading to the FDA approval and the new indication for that regimen. There was a 12-month OS benefit for patients who received durvalumab consolidation therapy after chemotherapy and radiation.

What has been the impact of combination chemotherapy and immunotherapy? 

Where do we stand with biomarkers of immunotherapy? 

In stage IV disease, [there are] 2 very important studies that were recently presented. First was KEYNOTE-189, which is a combination of pembrolizumab (Keytruda) plus chemotherapy versus chemotherapy alone. Second was the IMpower150 trial, which is a quadruplet regimen similar to what we saw in KEYNOTE-189, but using atezolizumab (Atezolizumab) in combination with carboplatin, paclitaxel, and bevacizumab (Avastin) versus carboplatin, paclitaxel, and bevacizumab alone.

That is a controversial topic right now. There is definitely synergy, and by combining drugs that work, you may get a better response rate, a better duration of response, and better OS. What chemotherapeutics are doing specifically, are improving the immune response so the immunotherapies can recognize and attack the cancers.

I still order PD-L1 [testing] on my patients, and I still use the cut point of 50% to define whether a patient should receive pembrolizumab alone versus pembrolizumab in combination with chemotherapy. This is for my patients with non—small cell adenocarcinoma and those with non–small cell squamous cell lung cancer. I know out in the community, people are now ordering PD-L1 expression. If you parse the data, no matter how you look at it, people who have a higher PD-L1 expression benefit with immunotherapy. What I like to do with my patients is weigh the risks and the benefits of each therapy. Why add chemotherapy to a regimen for a patient with a PD-L1 expression of 100%?

What are the limitations of a traditional tissue biopsy?

One of the other key biomarkers that is coming down the pike is tumor mutational burden (TMB). That is actually a lot more controversial right now. There are studies looking at it prospectively and retrospectively. The CheckMate-227 trial was recently presented by Matt Hellmann, MD, of Memorial Sloan Kettering Cancer Center, showing an improvement in patients who had high TMB. The controversy is, what is the definition of TMB-high? A lot of people are not using this assay and not testing for it, so we have a lot more work to do.

Liquid biopsy is a novel mechanism to identify circulating tumor DNA in the peripheral blood. By doing that, we are able to identify genetic alterations that we are then able to match patients to targeted therapies. Tumors are heterogeneous, so a metastatic lesion in the lung versus a metastatic lesion in the liver might have different genetic compositions. By testing plasma or blood, we are able to identify what alterations may be circulating in the body.

Tissue remains the standard of care, as we need to define histology. But, liquid biopsy is more accessible—it is easier to do and the turnaround time is quicker. Most of our liquid biopsy assays are able to turn around in 7 to 10 days, whereas standard next-generation sequencing (NGS) takes an average of 3 weeks. We did an interesting study where we compared the actual correlation or concordance between tissue NGS and plasma NGS and we did find that if you identified an alteration in the plasma, it was identified in the tissue about 97% of the time.

Could you expand on the importance of NGS? 

In what situations are liquid biopsies being used?

Are there any unanswered questions that remain with liquid biopsy?

However, the beauty of plasma and NGS for liquid biopsy was the turnaround time had an average of 9 days, whereas the turnaround time for tissue had an average of 21 days. Getting patients the results they need to get matched to targeted therapy quicker is better for their overall outcome.

Most academic centers are ordering NGS on all their patients. It is critical. When I talk to people out in the community, more people are adopting this practice. We have great targeted therapies for our patients, and it is time to identify the patients who will benefit from those drugs.

Liquid biopsies are critical in patients who you have a pretest probability of having a genetic driver alteration. Specifically, younger patients, and patients who are never-smokers. These are patients who you do standard immunohistochemistry for 

, and liquid biopsies are extremely helpful in identifying other alterations such as 

. [Additionally, they are helpful to identify other markers], such as 

 exon 14 skipping alterations, as well as 

 alterations—both mutations and amplifications.

The cost is an issue, as well as how physicians are ordering them. If they’re ordering them to monitor disease response or residual disease, there are no indications for that and no prospective studies showing their benefit. Where it is indicated clinically is upfront, or when you identify an alteration in a patient and you are assessing for a secondary resistance mechanism.

What is your advice on managing immune-related adverse events (irAEs)?

 exon 19 activating deletion and you start them on osimertinib (Tagrisso) and 1 or 2 years later they progress, getting a liquid biopsy makes a lot of sense to identify alterations such as 

 amplification, for which we have great clinical trials at NYU Langone Health’s Perlmutter Cancer Center.

Immunotherapy drugs are safe, well studied, and we know a lot about their toxicities. The key thing, is that if you are unfamiliar with these drugs, to talk to a doctor or team that is familiar with them. If you have any questions or concerns about a rash or diarrhea, reach out to your colleagues for help. There are very common irAEs, such as thyroiditis, dermatitis, and colitis, and if these are identified early, we can safely treat patients.

There has been some intriguing data with immunotherapy in small cell lung cancer (SCLC). Could you share your thoughts on any data that you have seen?

Other irAEs, such as pneumonitis, need to be taken more seriously, and we often will not expose the patient to the drug again. Working with your rheumatology and endocrinology colleagues, as well as dermatologists, is critical in building that infrastructure so you have a good referral system set up for patients when they need your help.

SCLC is a tough disease. Chemotherapy works very well with a great response rate rivaling 70% to 80%. Unfortunately, all patients relapse and have chemorefractory disease. There have not been any changes in the last 30 or so years until recently. We saw an FDA approval in the third-line setting, despite a low overall response rate of less than 10%. More recently with the IMpower133 trial, we saw the positive results of pembrolizumab plus platinum-based therapy and etoposide in the first-line setting with a 2-month OS benefit. Although that appears low on first glance, this is a large step forward in this field. What I am exciting about in this space is the multiple immunotherapy options available. We have a lot more to do here.

Joshua K. Sabari, MD, reflects on the rapidly advancing landscape of lung cancer.

State of the Science Summit on Advanced NSCLC | Conference