Therapy for Stage IV Non-Small Cell Lung Cancer without Driver Alterations: ASCO Living Guideline (Part 1)

An interview with Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, MI, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline." Dr. Jaiyesimi and Dr. Robinson review the latest recommendation updates for first-, second-, and third-line therapy in patients with stage IV NSCLC without driver alterations. Read the full guideline at www.asco.org/thoracic-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, Michigan, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on 'Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Guideline Update'. Thank you for being here, Dr. Jaiyesimi and Dr. Robinson.  Dr. Ishmael Jaiyesimi: Thank you for inviting me.  Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.  The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.  Dr. Jaiyesimi, do you have any relevant disclosures that are directly related to this guideline topic?  Dr. Ishmael Jaiyesimi: I do not have any financial disclosures. Thank you.  Brittany Harvey: Thank you. And Dr. Robinson, do you have any relevant disclosures that are directly related to this guideline topic?  Dr: Andrew Robinson: Yes, I do. I have had funding of less than $5,000 from BMS, Merck, and AstraZeneca in the past two years.  Brittany Harvey: Okay. Thank you for those disclosures. So, then let's talk about the content of this guideline update. So, Dr. Jaiyesimi, what prompted this guideline update, and what is the scope of the update?  Dr. Ishmael Jaiyesimi: The purpose of this guideline update is to update the ASCO and Ontario Health guidelines on the systemic treatment of patients with non-driver alteration stage IV non-small cell lung cancer last published in January of 2020.  The update is the result of potentially practice-changing evidence published since the last update. ASCO published the last full clinical practice guideline updates on systemic therapy for patients with stage IV non-small cell lung cancer that included those whose cancer did not have driver alterations in January of 2020.  The scope of evidence for the update guideline is made of ongoing or completed randomized controlled trials for non-driver alterations from 2018 to 2021. These updated algorithms provide recommendations from the ASCO expert panel and emphasized rapid changes in the management of patients with advanced non-small cell lung cancer and the importance of clinical research.  Brittany Harvey: Thank you for that overview, Dr. Jaiyesimi. So, then talking about those changes you just mentioned, I'd like to review the new or changed recommendations for this guideline. So, let's start with for patients with stage IV non-small cell lung cancer without driver alterations, and with high PD-L1 expression and non-squamous cell carcinoma, what are the updated recommendations for first-line therapy?  Dr. Ishmael Jaiyesimi: In addition to 2020 options for patients with high PD-L1, 50% or more expression, non-squamous cell carcinoma, and performance status of zero to one, and absence of targetable oncogenic driver alterations, clinicians may offer a single agent atezolizumab alone, or single agent cemiplimab alone, or a combination of nivolumab and ipilimumab without chemotherapy, or a combination of nivolumab and ipilimumab with two cycles of platinum-based chemotherapy. The number of acceptable options has increased. And each of the recommendations carries a strength of recommendation and quality of evidence with it.  Brittany Harvey: I appreciate you reviewing those options. So, then Dr. Robinson, moving on to the next category of patients addressed in this guideline, for patients with stage IV non-small cell lung cancer without driver alterations and with negative or low positive PD-L1 expression and non-squamous cell carcinoma, what are the updated recommendations for first-line therapy?  Dr. Andrew Robinson: Thank you for that question. So, in addition to the 2020 options for patients with negative, 0%, and low positive PD-L1 expression, with a TPS score of 1 to 49% and I'd add, unknown PD-L1, non-squamous, non-small cell lung cancer and a good performance status, clinicians may offer combination nivolumab and ipilimumab or combination nivolumab and ipilimumab with two cycles of platinum-based chemotherapy.  These are the additional recommendations and this gives an increased number of acceptable options, particularly for patients who cannot or choose not to take cytotoxic chemotherapy.  Brittany Harvey: Understood. Thank you for reviewing those options. So. then the next category of patients this guideline addresses, for patients with stage IV non-small cell lung cancer without driver alterations and with high PD-L1 expression and squamous cell carcinoma, what are those updated recommendations for first-line therapy?  Dr. Andrew Robinson: So, similar to the patients with non-squamous cell carcinoma for patients with stage IV non-small cell lung cancer that is squamous cell and a good performance status of zero to one, clinicians may also offer single agent atezolizumab alone or single agent cemiplimab or combination nivolumab and ipilimumab or combination nivolumab and ipilimumab with two cycles of platinum-based chemotherapy followed by ongoing nivolumab and ipilimumab. So, these are additional recommendations in this group as acceptable options for treatment.  Brittany Harvey: Great thank you for reviewing those options. So, then Dr. Jaiyesimi, what is recommended for patients with stage four non-small cell lung cancer without driver alterations and with negative or low positive PD-L1 expression and squamous cell carcinoma for first-line therapy?  Dr. Ishmael Jaiyesimi: In addition to 2020 recommendations, for patients with negative, TPS 0%, and low positive, with TPS 1% to 49%, PD-L1 expression, squamous cell carcinoma, and performance status of zero to one, clinicians may offer a combination of nivolumab and ipilimumab alone or a combination nivolumab and ipilimumab with two cycles of platinum-based chemotherapy.  Brittany Harvey: Great! So, then we've just reviewed the updates and changes to the first-line therapy recommendations. So, Dr. Jaiyesimi, were there any updates to second- or third-line therapy recommendations for patients with stage IV NSCLC without driver alterations?  Dr. Ishmael Jaiyesimi: For patients with non-squamous cell carcinoma who receive an immune checkpoint inhibitor and chemotherapy as first-line therapy, the clinician may offer paclitaxel plus bevacizumab in the second-line setting.  For the majority of patients with non-squamous cell carcinoma who received chemotherapy with or without bevacizumab and immune checkpoint inhibitor therapy, in either sequence, clinicians should offer the option of single-agent pemetrexed (non squamous cell carcinoma, non-small cell lung cancer), or docetaxel (all histologic types), or weekly paclitaxel plus bevacizumab, (non-squamous cell carcinoma, non-small cell lung cancer) in the third-line setting.  For patients in whom the initial treatment was not a chemoimmunotherapy combination should receive the treatment not given earlier that is platinum doublet chemotherapy (if the initial treatment was monotherapy with an immune checkpoint inhibitor, or dual immune checkpoint inhibitor therapy) and immunotherapy with an approved PD-1 or PD-L1 inhibitor in the second line setting (if the initial treatment was platinum doublet chemotherapy).  Brittany Harvey: Okay, thank you for reviewing those recommendations as well. So, then Dr. Robinson, what is the importance of these recommendation updates for practicing clinicians?  Dr. Andrew Robinson: These updates give an increasing menu of choices for patients and physicians, particularly in the first-line setting. The increased list of acceptable first-line options may help us physicians may run into situations where their preferred first-line option isn't available, or for other reasons shouldn't be given.  Now we recognize that given the increasing variety of options in the first line, it would be really nice if we could have guidelines, that say in this certain patient treatment with nivolumab and ipilimumab is recommended and in that certain patient chemotherapy plus pembrolizumab is recommended, and divide things up that way so that the right patient gets the right treatment.  However, the guideline committee did not feel that this was appropriate at that time as the only comparative data with these different strategies is insufficient, either population-based data or cross trial and network comparisons, that, however well done, do not have a defense against confounders and bias that a randomized study has.  So, the advances in drug development and research in non-small cell lung cancer in the past decade have made available multiple treatment options, particularly for first-line therapy for patients, and to some extent, this has also made the process of decision making in this context challenging for practicing clinicians, especially in the community and for patients and caregivers.  Clinicians need to understand patients' comorbidities as well as other variables that can potentially influence treatment decisions prior to making final therapeutic recommendations for any given patient, and also become comfortable handling a few of these regimens. Each of these are somewhat complex regimens with sometimes subtle and sometimes not-so-subtle differences that require expertise and appropriate treatment and monitoring.  So, with so many options available, it's important that clinicians get familiar with a few of them at least given that all of these regimens are now considered as appropriate standard of care regimens suitable for first-line therapy, it may also help justify physicians, researchers and ethics boards who are participating, designing and overseeing simple clinical trials that pragmatically ask the questions as to what should be used when.  So, physicians should simultaneously become familiar with these guidelines, familiar with different therapies, have expertise in a few of these therapies, and continue to stress cancer clinical trials that may improve outcomes, and also may help us determine which treatment for which patient at which time.  Brittany Harvey: Definitely, that makes sense. Thanks for reviewing these recommendations and also the limitations of the evidence around them. So, finally, Dr. Robinson, how will these guideline recommendations affect patients with stage 4 non-small cell lung cancer without driver alterations?  Dr. Andrew Robinson: Well, there are more options available which should be good but we wish what we meant when we say there are more options for patients, what we meant is that if one option doesn't work that other options are then available.  However, in this case, we mean that there are more options for patients for their initial therapy, particularly including more non-chemotherapy or reduced chemotherapy options.  It's difficult to imagine that many patients and clinicians will now discuss, say 8 options with patients with high PD-L1 lung cancer. Pembrolizumab, cemiplimab, atezolizumab, pembrolizumab with platinum doublet, nivolumab, ipilimumab, nivolumab and ipilimumab chemotherapy, and the majority of patients with high PD-L1 will likely continue to have single-agent PD-1 or PD-L1 inhibitors.  For patients with low PD-L1 lung cancer, the inclusion of nivolumab and ipilimumab without chemotherapy as a potential option may allow some patients to avoid chemotherapy toxicity and trade for other toxicities and choose a different therapy.  Patients who enroll on clinical trials where the comparator arm is any one of these therapies should be comfortable knowing that they are considered acceptable standards. The advancement in non-small cell lung cancer diagnosis and treatment would allow patients with stage IV non-small cell lung cancer without driver mutations who are eligible for immunotherapies with or without chemotherapy, a chance of living longer and the opportunity to participate in ongoing research to further move the ball down the field.  Brittany Harvey: Definitely. And, thank you for reviewing that as well. So, I want to thank you both for all of your work to review the rapid changes in evidence in this field and provide these guideline updates. I want to thank you again for your time today, Dr. Robinson and Dr. Jaiyesimi.  Dr. Ishmael Jaiyesimi: Thank you for having me.  Dr. Andrew Robinson: Thank you. It was a pleasure to be here.  Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. There's a companion guideline update on therapy for stage IV non-small cell lung cancer with driver alterations available there and on the JCO.  You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.