How to Treat Early Stage Non-Small Cell Lung Cancer in 2025

Intro Hello and welcome to another episode of the Oncology Brothers Podcast. I'm Rahul Ghosain here with my brother and Co host Rohit Ghosain. In our ongoing series of treatment algorithms. Today we're wrapping up our discussion on lung cancer and we're going to focus on early stage non muscle lung cancer where the treatment is with curative intent. There's a lot happening here from neoadjuvant chemo immunotherapy to actionable targeted treatment options to mature data on immunotherapy as consolidation. We have a lot to cover in this episode and we're excited to have a friend and a colleague, Dr. Deepa Rangachari, a thoracic medical oncologist and the fellowship Program Director for the Hemong program at the Beth Israel Deaconess Medical Center Depot. Thank you so much for joining us. Speaker 2 Rahul Rohit, thanks for the invitation. Look forward to a spirited discussion. Speaker 3 Deepa, welcome. So there's a lot happening. As Rahul stated, perioperative neoadjuvant adjuvant approach. So let's dive right in. For stage one, surgery still remains the standard of care and where surgery is not possible, we resort to SBRT. But stage 1B and beyond, we have multiple treatment options. Before we touch on treatment options, it is important to state that staging with lymph node evaluation and brain MRI is important. NGS is critical as well with two approved agents, osimertinib for common EGFR mutations and alectinib for AL positive mutated disease, Deepa. Can you please walk us through your treatment approach? Treatment Approach If one does not have any actionable mutation, how are you deciding perioperative chemo, immunotherapy, neoadjuvant or adjuvant? Speaker 2 The first point here is before you even talk about therapeutic selection. Optimal therapeutic stratification necessitates mandatory radio graphic staging, PET and MRI brain, mandatory pathologic nodal staging with emphasis of mediastinal nodes, genomics and multidisciplinary evaluation. The critical first question always is, is the patient candidate for surgery or not? Assuming that you've done all of those things and you know that you're dealing with stage, you know, 1B to 3A non small cell lung cancer and someone who is a candidate for surgery and there are no actionable genomic alterations, then I think the field is moving towards favoring neoadjuvant chemo immunotherapy with consideration of adjuvant or fully perioperative therapy depending on the outcome at the time of surgery. And specifically what I mean by that is recent updates from the Checkmate 816 trial, which was neoadjuvant chemo immunotherapy followed by surgery with post operative therapy. Dealer's choice has shown us that patients achieving A pathologic complete response rate have an incredibly high likelihood of event free and overall survival. I would generally counsel a patient to expect to have perioperative therapy if they've achieved A pathologic complete response. I think now we can feel pretty reassured it's at having a discussion after surgery as to whether you're going to continue adjuvant checkpoint inhibitor therapy or not. Speaker 1 Deepa, you touched on the recent update on Checkmate 816 from ASCO 2025, which was presented by Doctor Patrick Ford. PDA1 as a biomarker In this presentation, we saw that majority of the benefit is being driven by PDL 1 positive disease. Historically, we've not relied on PDA one as a biomarker here, but are you adopting this in your practice or regardless of PDA one, everyone is going to get new adjuvant chemo immunotherapy and then you rely on PCR as your surrogate marker. Speaker 2 Yeah. So I think predictive biomarkers here are one, to select optimal therapy and importantly to not administer a therapy that is likely to be ineffective for a patient. So for example, patient whose cancer has an EGFR mutation, we know that immune checkpoint inhibitors are ineffective. So biomarkers make sure you're offering effective therapy. And I think frankly they're to help predict how rigorously beneficial the therapy will be. But I think at the end of the day, what matters is how the biology of the cancer has been altered by the therapy. And so personally I would say that regardless of tumor PDL, one expression and the pathologic complete response has been achieved. Then I think we can feel very good about having conversation about whether or not post operative therapy needs to be continued or not. And to me, the high PDL one really just tells us that we can expect those patients have the greatest likelihood of achieving a path CR. Speaker 1 I know this will keep coming up over and over. Role of CTDNA in cancer therapy Any role of CTDNA here? Speaker 2 I think the field is evolving in that direction, but as of right now, I would say this is really an investigational and exploratory tool. I would not advocate for routinely using it. One of the biggest challenges with all of these things are that if you achieve A pathologic or biologically favorable outcome, whether it's complete response or CTDNA negativity, that's great. But what we don't have yet are adaptive therapies where if you didn't achieve the path CR or clear your CTDNA, we don't have some biology adaptive therapy where we're going to switch gears and do something else. Now after surgery, I worry about routinely using tools that don't allow us to deliver a better care model. Once we know how to adapt therapy with that information, I would be delighted to see us use it more routinely. Speaker 3 All righty, for our audience, CTDNA here's only for clinical trial is not FDA approved here right now. And with regards to Deepa, how you started with multidisciplinary that is the key 1 cannot undermine the importance of that. And now tying in the role of adjuvant IO especially once one has achieved PAT CR that has been the struggle even in breast cancer and now bladder cancer where we are using more and more perioperative approach. But that was all for one does not have any actual mutations. Now one does have actionable mutation where we did the NGS and the treatment choices are ocmertinib and alectinib. Ocmertinib based off of ADORA trial which showed OS where ocmertinib is for three years, Alectinib based off of Alina trial where alectinib here is for two years. If one has one of these actionable mutation that is common EGFR or out positive disease, any role of chemo at all, or one can rely on these targeted agents completely. Chemotherapy sparing regimens Great question. The keenness here is for chemotherapy sparing regimens and your question is critical. The data that we have from ADORA does not support use of azimertinib in place of chemotherapy. It supports use of azimertinib sequentially following chemotherapy. There were there was a small proportion of patients in this trial who did not get chemotherapy at provider discretion, but that was a minority of patients and the vast majority of patients who who have the maximum risk of recurrence and maximum benefit from adjuvant therapy did get chemo followed by osmertinib. Contrast that to the Alina trial which did randomize patients to receive either adjuvant platinum doublet chemotherapy or adjuvant electinib for two years and then that setting electinib demonstrated a clear benefit. I will say though that you know, in discussion with other lung cancer experts in the field, many of us still feel that in a patient with higher risk features, node positivity, certainly mediastinal lymph node positivity in the adjuvant setting with an ALK gene rearrangement. Many of us in an otherwise chemotherapy eligible and willing patient would still offer adjuvant platinum doublet chemotherapy and then give alectinib for two years, even though that is not technically how it was studied in the Lena trial. And the reason for that is, you know, we know that these tyrosine kinase inhibitors in the right genomically defined group do an incredible job of suppressing disease, but still concerned that we are suppressing disease rather than eradicating disease, which whether you like it or not, platinum doublet chemotherapy has proven to have the ability to eradicate disease with a perhaps neatest but well established survival benefit. Speaker 1 Deepa, you brought this up, there's overall survival benefit that adjuvant chemotherapy. Right now in my clinic, I have these two patients, stage 1B with sensitizing EGFR mutation. We decided not to give chemotherapy and just rely on osmertinib. I have a stage 3A out positive patient who after surgery got chemotherapy and is now on the lectinib. So I think there are some nuances and appreciating what's the right treatment combination for that patient in front of you. Rohit, one big concern in our clinic ends up being for EGER for mutated disease that's CNS involvement, DEEPA and adjuvant settings. Routine CNS Surveillance in Adjuvant and Depreciation Settings How frequently are you getting that brain MRI as part of her surveillance scans and otherwise asymptomatic patient? Speaker 2 In a patient treated with curative intent, there really are no rigorous evidence based or expert consensus guidelines to recommend routine CNS surveillance. Even in patients with metastatic disease, there are not clear or consistent guidelines for how and when to do that. Even though many of us will do that in the metastatic setting, we don't routinely have guidance or recommendations to do so in the curative setting. So upfront brain MRI for sure, but no clear recommendations or guideline for surveillance brain MRI for patients receiving adjuvant therapy with these mutations or alterations. Speaker 1 All right. At ASCO 2025 we also saw data from NEO ADORA trial, but right now the approval is in adjuvant settings. Now let's switch gears to unresectable stage 3 disease where our standard of care is concurrent chemo radiation followed by one year of dirvalumab based of Pacific trial or again olzomertenib after concurrent chemo radiation for that common each year for mutation disease based off Laura trial. Standard of Care for Stage 3 Non-Metastatic Non-Small Cell Lung Cancer But here it's olzomertenib that's indefinite. Deepa, you briefly touched on it. Are we just suppressing the disease? But before we get into the EGFR mutated disease, can you first touch on the mature data and standard of care based of specific trial? Speaker 2 Yeah. So I think this is probably the most straightforward care paradigm now for a non metastatic non small cell lung cancer. If the patient has locally advanced disease and is not a candidate for surgical resection, then concurrent platinum based chemo radiation followed by one year of dirvalumab is the recommendation. Importantly, molecular profiling matters a lot here. If you identify an actionable EGFR mutation, then in place of dirvalumab you're going to give osmertinib. It's an open question as to whether other molecularly defined subgroups that have clinical and patient specific factors similar to those of people who have EGFR mutated lung cancer. So those with ELK or Roz gene rearrangements, do we, what do we do there? And I think the answer in my mind is I would not advise dirvalumab for those patients. And it's an open question as to whether or not we should apply same evidence about targeted therapies as consolidation in Stage 3 disease. Speaker 3 Thanks for covering that Deepa to rely on this chemo radiation approach followed by dirvalumab, which is the Pacific. Curative intent vs curative reality We've tried this in small cell lung cancer and is in fact the standard of Care now with based on Adriatic study. But there are balimab is for two years now switching to the Laura trial which Rahul was just recently talking about with indefinite osimertnib, which seems daunting. But again in limited stage setting. When we are saying this, we are treating curative intent but with lifelong treatment. Are we still going for a cure here? And any role of CT DNA in this particular space? Speaker 2 Yeah, excellent question. I think it's recognizing from a pragmatic standpoint that cure in terms of how a patient lives can have two different looks, true eradication and then highly effective suppression of disease. The honest truth is that historical and modern day data from the Laura trial remind us that few patients with stage 3 disease are actually cured. The outcomes in patients with EGFR mutated locally advanced disease after chemo radiation looked particularly abysmal in the Laura trial. And so I think in this setting we are seeing with curative intent. And yet there's a difference between curative intent and curative reality. Indefinite osmertinib is one way to translate curative intent to curative reality. As long as patients are able to continue taking the medication, it would be wonderful. And I think we will see strategies where we will be able to use CT DNA after chemo radiation to understand which of those patients we are achieving curative intent or reality by chronic suppression of disease versus true eradication of disease. And that may allow us then in patients who are having difficulty adhering to the daily routine of a pill by mouth every day, diarrhea, rash and all the rest for life. It would be great to in the future, I think we will have ways to use CTD and A to figure out how and when can we de escalate therapy and monitor people. And if we see a signal that the disease that was not eradicated is now sort of evolving again, turn around and suppress it by restarting Osmertem. So I think there's going to be some opportunity for dynamic therapeutic modeling in this setting using CTD and a. Speaker 3 Right. We consider these oral treatment regimens rather benign or well tolerated, but there are serious side effects that are associated with it especially when we tie in quality of life aspect. Now as you were talking about other biomarker testing with regards to AL positive, at least in my setting, the important key factor here is patient shared decision making where we do not have FDA approval. Biomarkers for AL-positive patients Do you use this off label at all after chemo radiation? Speaker 2 I would definitely speak with a patient about it, acknowledging the limitations of not having rigorous prospective data in this particular setting and really trying to understand for a patient what version of the cure is most aligned with their wishes and quality of life. I recently had this discussion with a patient who did fine with surgery but struggled with side effects of systemic therapy with the thought of having to take alectinib every day. This was in a post surgical setting but I've seen patients like this after chemo radiation too. We had a conversation and this patient said to me I really don't want to live my life taking multiple pills, you know, twice a day. So I hear what you're saying, but I'm going to bypass this option for now. And if and when my cancer comes back, I will be ready to take the medicine. And then I have other people who say the look of cure that they want is to do anything and everything so that the cancer is never seen again. And in that person, it's probably best aligned to give them the opportunity to have a lectin. So I would have the discussion and then really try to align the plan with the patient's goals and wishes. Speaker 1 And the other conundrum here is when we're relying on that off label indication is how long, how long are you going to keep on electronic because again, are we just extrapolating that data from Laura trial? But this is a good segue. We keep saying how long because there are some side effects, Deepa, if you don't mind touching on some brief side effects and clinical pearls around ultrameritinibiline, alecnib so that we can keep our patients on these medications for longer. Common side effects of UMRT/ALEC The dosing, some common side effects. What should we be aware of in the community settings? Speaker 2 Yeah, awesome. Earnib is really the poster child in my mind of being able to balance highly effective therapy with something that has side effects but can be managed with lifestyle and pharmacologic interventions. As many of you know, most common things include skin toxicity. Skin toxicity can include a variety of things. That includes the nails too, right? So it's not just the acneiform rash, but it can also be dry or cracking skin, nail bed changes, brittle nails. All of these things ask about, look for, and validate people who describe this spectrum of things commonly managed. I remind a lot of my patients, if you didn't have a skin care routine before this diagnosis and you're going on osmertinib, please adopt A skin care routine. Use of topical emollients twice a day, use of good sun protection with either protective garments or sunscreen when you're out and about, and then topical Clindamycin and topical hydrocortisone spot therapy for more focal patches of erythema, itching or acneiform rash. I have a very low threshold to start oral tetracycline therapy with doxycycline for those patients who have more diffuse skin toxicity. It really suppresses the acneiform rash very nicely. If they can overcome the GI distress associated with doxycycline, it can work well. Some patients go on it for a while and then continue on oxymertinib and they are able to wean themselves off the doxycycline. I think it's just worth not being hesitant to started just because someone get started on it. It doesn't necessarily mean that they will require antibacterial use for the duration of therapy. Diarrhea, of course, is well known and can be very bothersome. Grade one diarrhea still means you're going up to four times or more over your baseline. That's unpleasant. I work with people to understand the cadence of their bowel movements. We find it's helpful to have a schedule that they take loperamide in an anticipatory fashion rather than waiting for loose bowel movements to start and then playing catch up. Elected him. On the other hand, a little bit, some of the side effects not so straightforward to address. So things like fatigue, nausea, diarrhea, okay, we can manage those. But some of the other side effects that can be really plaguing with this drug can be things like lower extremity ramping, heaviness, edema. Those are really hard things. Frankly, there's no easy doxycycline that you can prescribe for that. And so in those and you're nodding your heads, you've probably seen this, you know, in those patients, sometimes really the best way to get around it after a while is they do require a treatment holiday or a dose reduction. So I would say more commonly with the lectinib, you might find that you need to pivot to dose reduction or treatment break. I'd say a little bit more commonly than I find is often needed for osmertnib. But don't forget osmertnib at a dose of 80 milligrams every other day or 40 milligrams daily is still highly effective. Speaker 1 Yeah. I want to reiterate that more and more studies and data export that even when we're decreasing that dose, these patients still have good outcomes. So coming back to that quality of life and the benefit that we're chasing has to go hand in hand. Conclusion Deepa, we've covered a lot in this last few minutes. The early stage non small cell lung cancer landscape is moving fast and it's on us in the community settings to stay up to date to make sure we are providing that best gear close to home to all our patients. Deepa, thank you so much for taking the time to walk us through your treatment paradigm. For our listeners, let us go over a quick recap today with Doctor Deepa Rangachari from Beth Israel Deaconess Medical Center. We touched on early stage non small cell lung cancer where treatment is with curative intent. Angius testing upfront is critical as we now have Alzheimer Tinib approved for EGFR positive disease and alectinib for ALP positive disease. Recently, we've also seen updated overall survival in neoadjuvant 3 cycles of nivolumab with chemotherapy in resectable non small cell lung cancer with five year overall survival roughly being 65% versus 55%. Speaker 3 Right. And Rahul, it's important to reiterate that Ocmertinib in adjuvant settings is for three years based off of ADORA trial and alectinib is for two years based off of a Lena trial, whereas Ocmertinib is currently approved lifelong. Or unresectable stage 3 after concurrent chemo radiation based off of Laura trial. Speaker 1 Yes, absolutely. And for disease that is not driven by a targeted mutation, the current standard of care remains concurrent chemo radiation followed by duvalumab for one year based off Pacific trial. Thank you all for tuning in. Be sure to check out our other lung cancer episodes in this treatment algorithm series. We are the oncology brothers.