The improvement doesn’t just come in the neoadjuvant space. In the past, we all got used to adjuvant therapy. The patient who went to Dr [Nasser] Altorki’s clinical trial got surgery. After surgery, he was found to have occult nodal disease. There are still a large group of patients we need to consider for adjuvant therapy. Can I ask you to comment on developments in that adjuvant space, where we’ve seen tombstones as opposed to milestones in the past, such as radiation and VEGF targeting? So many things have failed, but recently, there’s some excitement, right?

 We have 2 new studies that have helped us improve outcomes in the adjuvant setting. They are easier to interpret because they latch onto the standard of care that we previously used, which was predominantly surgery followed by adjuvant chemotherapy and then an immunotherapy approach.

The first one is the IMpower010 study [NCT02486718] with adjuvant atezolizumab vs best supportive care. It was a large study that Dr Heather Wakelee presented about 2 years ago. We saw interesting progress for tumors greater than 4 cm with PD-L1 positivity independent of mutational setup, especially in PD-L1–high tumors greater than 50%. We have seen some very significant improvement in disease-free survival and, more recently, in overall survival. The question still is what to do with those that we traditionally think of as not immunotherapy responses: the 1% to 49%’s, the EGFR, and the ALKs?

We do not see the same strength of signal for improvement for those subgroups. A lot of the biomarker lessons from the metastatic space have transferred into IMpower010. In those, an approval for PD-L1 greater than 1%. There has to be much more nuance placed on the biomarker setup to guide a potential benefit. Is it safe to hold? Will the outcomes really change with overall survival? Especially for the PD-L1 lows from 1% to 49%, this hasn’t been fully answered yet.

The [KEYNOTE-091/PEARLS] study [NCT02504372] was a little bit different. It was a large, randomized study looking at a similar patient population with a co–primary end point of analysis for PD-L1 greater than 50%, and then in the PD-L1 agnostic patient population for the adjuvant setting. To my surprise, some of the biomarker lessons we had before were turned upside down. We saw a PD-L1 agnostic benefit for PD-L1–negative lows and highs, and staggered and certainly improved for the PD-L1 highs. This [then ended with] an approval for all-comers’ PD-L1 levels.

This is one where I have difficulties and would love to hear my colleagues’ thoughts on it. Where should we group in the PEARLS study for treatment? Both of them have chemotherapy requirements, so at least 1 cycle of chemotherapy is mandated by the label. It was a smaller subset [that was] not felt to be sufficient for full analysis. I think that patients who are eligible in this setting derive an overall survival benefit from adjuvant chemotherapy. So if an adjuvant therapy approach is chosen, I think it should be offered and evaluated for adjuvant chemotherapy eligibility. I do not want to take any shortcuts here for treatment of patients who have the option to skip to immunotherapy directly. I offer this option to all of my patients in PD-L1 levels greater than 50% if the biomarker setup excludes EFGR or similar oncogenic drivers. For those with levels 1% to 49%, I am still on the fence and would have to have a very detailed discussion with the patients. I certainly have not thought about this for PD-L1 negatives. We have a real tumor sample, so we get a pretty representative idea of how PD-L1 looks. If you have tumor sample [that is] PD-L1 negative, in my practice, I would not consider adjuvant immunotherapy.

A terrific summary. You brought up so many great points on the controversy between the 2 study results. It’s very hard to read. Looking at the discrepancies between the 2 studies, are you sticking with the known biology and logic, or are you willing to yield to the broader approval of pembrolizumab for the TPS [tumor proportion score] agnostic, including zero-patient population?

 There’s no right answer to this question. I think patient-informed discussions are important here. The data is the data at the end of the day. However, in the IMpower010 study, it does appear that the PD-L1–high subgroup is really deriving that benefit, so I would agree with Dr Dietrich [about] atezolizumab’s clear benefit in the PD-L1–high population. I am inclined to recommend pembrolizumab for those with 1% to 49% levels in the adjuvant setting, and particularly when you’re talking about lymph-node positivity, occult N2 lymph nodes, where your likelihood of recurrence is very high. I do not know if we should be looking at this as we do with immunotherapy monotherapy in the metastatic setting where the IO [immunotherapy] is in a vacuum.

If you are looking at chemo then immunotherapy, what is the best comparison there? Is it like a KEYNOTE-189 [trial regimen]? I know that’s combination [therapy]. It is not sequential. But maybe we can’t create an analogy to the IO monotherapy studies in the metastatic setting. The PD-L1–negative population is definitely perplexing. I am inclined to have the discussion and offer the therapy to someone who has high risk for recurrence, a large primary tumor, or occult N2 disease involvement.

People may ask what I am going to do when patients recur. Will I be utilizing these chemotherapy chairs for patients who may not need it? My argument there is whatever we can do to prevent a recurrence and to prevent someone from having metastatic disease, whatever we can do to promote cure, trumps what we’re going to do in the metastatic setting.

 My clinical practice is similar in that we use PD-L1 [grading]. I do not consider atezolizumab unless the PD-L1 is above 50%. If we are going toward using neoadjuvant immunotherapy, how can we actually interpret this data? Could you use pathCR [pathologic complete response] to determine if adjuvant therapy is indicated? I have used neoadjuvant and adjuvant equivalently. It might a be bias of my institution, but in general, that is what we have clinically seen play out in terms of how we have used these FDA approvals in our clinic so far.

Both approaches are here to stay, so all of us need to stay comfortable in terms of learning by literature and adapting it to the patient in front of us. Martin made a very good point in terms of the surgical specimen providing a great sample for TPS testing. In fact, at our tumor board, we have decided never to accept the presurgical cytology for biopsy when making adjuvant decisions. But we are doing it under another surgical specimen. In reality, what’s the difference between 0% vs 1%? If you ask a pathologist, they can make anything 1%, if you ask them todo that. There is a lot of relianceon a technology that’s not perfect for this context, but it is the best we have. That’s just the reality.

Videos

Switching their focus to the adjuvant setting of resectable NSCLC, expert panelists identify treatment options in this setting and review the clinical data behind them. 

Adjuvant Treatment Strategies in Resectable Non–Small Cell Lung Cancer 

This patient came to Martin from rural Florida, and the biopsy wasn’t sufficient for any type of testing. What do you do in such a case?

 It is a very challenging situation when we think about the trial design of CheckMate 816 [NCT02998528]. We compared neoadjuvant chemotherapy [with] neoadjuvant chemotherapy IO [immunotherapy]. It helps us to use something very powerful as stand-alone data. The intervention arm was so strong that it was very convincing. But how much response do we actually expect from chemotherapy? Is 3 or 4 cycles enough? How do we approach follow-up care?

When you have a patient who has a pathological complete response, this may not be as difficult…but you do want to know what their molecular [profile is]. In this case, it may be necessary to get a repeat biopsy. I have not been very successful getting enough circulating tumor DNA [ctDNA] from liquid biopsies and early-stage disease. The question is, what are you going to do with [a patient] once they’ve had surgery and a pathological complete response?

The other question is, how do you guide patients for prognostication? Melanoma [research] is always spearheading these efforts for our novel immunotherapy approaches, showing that the intact tumor microenvironment really supersedes the resected tumor specimen and adjuvant immunotherapy. I think it is going to come out the same way in lung cancer.

How do you guide a patient prognostically if you have a squamous PD-L1 negative [result]? The expectation is very different than when you have a 

-mutant PD-L1 90% adenocarcinoma. Molecular testing is now at the stage where we should use it across all stages of lung cancer, from stage I through stage IV, to guide therapy selection and therapy treatment. I would not want to give neoadjuvant immunotherapy to an 

-mutant patient. We’re going to give an outpatient neoadjuvant immunotherapy. It is very important to have this up front. It makes it more challenging in the multidisciplinary team to get the surgeons to be on board with the idea of getting tumor tissue. Especially for tumors in ... distribution, where no lymph node disease is positive in tissue procurement, it can be particularly difficult. In my book, it has to be done for every patient who requires systemic therapy. It poses the same challenge that we had in stage IV disease. We have to really get good about doing biopsies and selecting good biopsy approaches for patients to guide their therapy the best way possible.

I saw that Kristen was shaking her head when ctDNA was mentioned. What is your team doing at [Johns] Hopkins, in terms of maximizing the tissue and minimizing the turnaround time, patient navigation, tissue stewardship, and things of that nature? What can we do to maximize the potential of that tissue to inform us?

 We are actively struggling and working on that. We were all getting super excited about next-generation sequencing, adding all these genes, and doing all this great testing. Now we’re headed back to single-gene IHC [immunohistochemistry]-type things. We are [moving] away from super-sensitive things and more toward turnaround time. We are trying to get assays back in 3 to 5 business days, rather than in 10 to 15 business days. I think that has been our biggest issue. There are logistical parts to this problem. What sample is being sent to what lab? What institution? Are you getting a block, are you just getting a few slides? Is that enough? How much tissue did they actually get on a biopsy if the tumor is small or necrotic? Those are all things that we have seen in the past month in our…clinic. Tissue acquisition, testing, and turnaround time are huge unmet needs in the neoadjuvant setting.

Interestingly, all of these studies are doing something different in terms of duration of therapy. There are a lot of unmet needs and unanswered questions that we need to think about in terms of how to operationalize and select options in this scenario, how to use what biomarkers we have, and what we’re trying to look for moving forward.

Certainly, a lot of challenges and a lot of new questions, but also, better outcomes for our patients. I think we’re all embracing that new challenge, in a way.

Shared insight from key opinion leaders on the value of molecular testing in patients with resectable non–small cell lung cancer and how it can be applied. 

What is the Role of Molecular Testing in Resectable Non–Small Cell Lung Cancer?

Kristen, could you introduce us to the evolving neoadjuvant literature and how that might impact this particular patient’s case?

 There has been a lot in the neoadjuvant perioperative space in the past year, and I think we are going to be seeing an explosion of more data and lots of questions about this soon.

Right now what we have available to us is already approved. We know neoadjuvant chemotherapy is an option. But what has been recently approved is the CheckMate 816 [trial] [NCT02998528] data, looking at adding neoadjuvant nivolumab to chemotherapy. Both the patient and tumor characteristics would make this patient a viable candidate for a potentially neoadjuvant approach. The multidisciplinary team should be available to the patient in real time because everybody wants treatment decisions quickly. This is a potentially curative situation, so we want to make sure that everything from the pulmonary function test to the surgical evaluation to the PET to the brain MRI are all done quickly.

We are thinking more and more about how to use molecular data to inform these options. We know the CheckMate 816 data excluded EGFR- and ALK-positive tumors. Trying to integrate that amount of molecular testing into the neoadjuvant space is a huge logistical barrier across a lot of clinics, so as a community, we need to think a lot about that. Dr [Patrick] Forde published the study in the 

] in 2022. It was a phase 3 study looking at neoadjuvant, 6 weeks [of] nivolumab, plus chemotherapy, compared to chemotherapy alone. Their primary end point was pathologic complete response and median event-free survival, which ended up being about 31.6 months at the first presentation. Then the pathologic complete response was 24%, compared to 2% with chemotherapy alone. That was statistically significant, and it’s really exciting for our patients, which led to its FDA approval.

Interestingly, we saw trends toward benefit regardless of PD-L1 status. We saw trends toward improvement in outcome, especially in higher-stage disease. We saw patients were able to tolerate the therapy and the surgery. The neoadjuvant immunotherapy did not preclude them getting to the surgery safely, so our surgeons are well-situated to perform the lifesaving surgery. All of that was really exciting data, and it has led to us thinking about this much differently than even a year or two ago.

What else has come out is the NADIM II study [NCT03838159], which was looking at neoadjuvant chemotherapy [with] nivolumab, followed by 6 months of adjuvant nivolumab, compared to chemotherapy alone in stage III disease. That data was recently presented, which showed significantly improved pathologic complete response. They also were able to provide some PFS [progression-free survival] rates at 12 and 24 months, and also showed significantly improved overall survival rates at both 12 and 24 months. I think these studies are the first of many to show us what potential benefit there is for immunotherapy in this early-stage setting. We’re going to have a lot of data coming at us, about how to select patients, what to use pre [and] post [therapy], [and] what pathologic complete response really means. Can we use that to extrapolate who needs IO [immunotherapy] later on? We are going to hear about adjuvant immunotherapy soon, and how to integrate all of that into this.

The last study that I should talk about is the AEGEAN study [NCT03800134], which was just announced. [It’s] a phase 3 study using durvalumab in combination with neoadjuvant chemotherapy that showed a statistically significant and meaningful improvement in pathologic complete response, compared [with] chemotherapy alone. I would love to hear what everybody is thinking about this data and how you are treating patients. I can certainly say it has changed how I’ve been treating my patients. This is something we’re trying to offer to most people, especially if they are deemed to be surgically resectable.

This has been transformational. Just to put it in perspective: The pathological CR [complete response] rate for the TPS [tumor proportion score], high-positive patients, went from 5% to 45%. By the time of surgery, half of the patients are tumor-free. We have been hearing surgeons telling us that they have taken the whole thing out. Now we can tell them that we medical oncologists made the cancer go away by the time they take the patient to the OR [operating room]. Do you look at the TPS in your treatment selection? What are you thinking in terms of when you’re seeing a patient in front of you?

 I would say that the PD-L1 is less informative to me for whether or not to go with the CheckMate 816 regimen. For me, it’s the mutational analysis, which I think is a very difficult situation in the neoadjuvant setting. In that scenario, molecular testing is the easiest. You’ve got tons of tissue [and] patients are recovering from surgery. In the neoadjuvant setting, when you are dealing with a small bronchoscopy sample that needs some limited IHCs [immunohistochemistries] and then you do full NGS [next-generation sequencing], the question is, do you do a limited panel where you look for EGFR, ALK, or KRAS, to get that information before you start systemic therapy? Do you give a cycle of chemotherapy alone and try to do the full NGS and then add in IO, and give three cycles of [the CheckMate 816 regimen]? I am more concerned with turnaround time.

Focused discussion on the selection of neoadjuvant therapy in patients with resectable NSCLC in light of recent clinical trials.

Resectable Non–Small Cell Lung Cancer: Neoadjuvant Treatment Strategies 

 titled “Recent Updates in the Role of Immunotherapies in Non–Small Cell Lung Cancer: Translating Evidence to Clinical Practice.”I’m Balazs Halmos, MD, MS, from Montefiore Einstein Cancer Center, and joining me today in this discussion are my colleagues.

 Hi, my name is Kristen A. Marrone. I am a thoracic oncologist at Johns Hopkins in Baltimore, Maryland.

 Hello. I’m Martin Dietrich. I’m a medical oncologist with Florida Cancer Specialist at the University of Central Florida in Orlando.

 I’m Joshua Reuss. I’m a thoracic medical oncologist at Georgetown University. Happy to be here.

Thank you so much for joining us. Today we are going to discuss the most recent updates in immunotherapy for advanced non–small cell lung cancer. We will discuss the latest research in the field and the impact of recent clinical trials on making decisions around treatment selection.

Let me introduce a patient case so that we can start our discussion. This is a patient from my practice who I saw a couple of weeks ago. A 60-year-old African American man, heavy smoker [in] the past. He comes in with a couple of months’ history of left-sided back pain. Got some CAT [computed axial tomography] scans. The CAT scans show a 5-cm lung mass in the left upper lobe, invading the rib cage. The patient undergoes further testing, including a PET [positron emission tomography]-CT scan that does not suggest any nodal uptake or metastatic disease. A brain MRI is also done. The patient gets a CT-guided biopsy that shows squamous cell carcinoma. It appears to be [a] chest wall invasion, maybe a T3 and 0, stage IIB squamous cell lung cancer, and we need to make some big decisions for this patient [pertaining to] the treatment selection.

Is there some more information that you would need prior to making a decision? What would be your [top] choice?

 We would need to understand the patient’s performance and functional statuses. Then we could think about if we are going to attempt neoadjuvant therapy prior to definitive surgical resection. And then we need to understand the staging of the disease. We would make sure there is a brain MRI that’s done to complete that. We can then talk with the patient about the exciting new therapies that are available to him, depending on what those results are.

Fortunately, a brain MRI was done, and it’s negative. The patient doesn’t seem to have a lot of comorbidities. Is there anything else you wouldwant to have in your hands to make a treatment decision? What would be your recommendation for such a patient?

 I would be sure to do a PET-CT scan to rule out any distant metastatic disease. A full NGS [next-generation sequencing] profile might be [too much] for squamous cell lung cancer. But I would want to get the basic NGS testing for actionable drivers, as well as PD-L1 results, so I can better guide my patients in what they would expect in a neoadjuvant approach. I think the surgeon’s input is super important here, too. We want to know, is this truly resectable, or do you have to call your radiation colleagues?

We’ve seen some major surgical updates with the Cancer and Leukemia Group B [CALGB] study reading of Dr [Nasser] Altorki’s 

paper ... But we need to remember that is not for this type of case. The CALGB study and the Japanese study were very small, [focusing on] less than 2-cm peripheral lesions, suggestive of sublobar resection. Resections achieved excellent outcomes, matching that of lobectomy. For select patients with very small peripheral lesions, that might be an appropriate approach.

In our case, we need the technical expertise of an excellent surgical team. The chest wall might be borderline for resection. What’s your thought in such a case? Would the TPS [tumor proportion score] make a difference as to your treatment selection, or anything else?

 We need to consider lung function and surgical resectability. This is the last piece of the puzzle, from a patient perspective. I do not really know that we have a good head-to-head data comparing radiation [with] neoadjuvant approaches in this case. This would certainly be my big discussion. We have seen some very exciting data for neoadjuvant chemotherapy immunotherapy options, especially if there’s a PD-L1 score that would be suggestive of a good response, to see if we can actually convert this. Sometimes we are trying these approaches and it may turn out that a patient does not respond as well. In retrospect, this is more of an induction chemotherapy rather than a truly neoadjuvant therapy. The decision about surgery is really one that we make after neoadjuvant therapy, as much as we do it beforehand. We have 2 good options here. The early introduction of immunotherapy in an intact tumor environment is a very useful contextualized use of immunotherapy. In a patient like this, we would follow the CheckMate 816 [trial] [NCT02998528] regimen: give 3 cycles of neoadjuvant [chemotherapy immunotherapy], then image again and see if the patient has converted. If not, then I would proceed with chemoradiation, followed by immunotherapy.

We shouldn’t forget about radiation being a definitive curative strategy for many of our patients. Especially, if the PET scan suggested some nodal disease, and maybe we would confirm it with an EBUS [endobronchial ultrasound]. If you have a borderline-resectable patient with nodal disease, the conversation might shift. But the PET-CT didn’t show any of that. A careful EBUS was done, and the patient is not negative.

Expert oncologists reflect on key factors that aid in the selection of therapy for patients diagnosed with resectable non–small cell lung cancer (NSCLC). 

Joshua Reuss, MD, Georgetown Lombardi Comprehensive Cancer Center

Articles

Adjuvant Treatment Strategies in Resectable Non–Small Cell Lung Cancer

What is the Role of Molecular Testing in Resectable Non–Small Cell Lung Cancer?

Resectable Non–Small Cell Lung Cancer: Neoadjuvant Treatment Strategies

Key Decisionmaking Factors in Resectable Non–Small Cell Lung Cancer