CE / CME
Pharmacists: 1.25 contact hours (0.125 CEUs)
Nurses: 1.25 Nursing contact hours
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: September 30, 2022
Expiration: September 29, 2023
Edward B. Garon, MD, MS: Switching gears, let’s now discuss important questions related to the second-line setting and beyond.
First, returning to our survey question about liquid biopsy, please recall that approximately two thirds of participants reported testing at disease progression.
Dr. Socinski, since I asked you about biomarker testing above, let’s start with you. What is your practice regarding biomarker testing at disease progression and does liquid biopsy play a role?
Mark A. Socinski, MD:
In addition to performing liquid biopsy at diagnosis, as we discussed earlier, I also do liquid biopsy testing at progression. I routinely used this approach when EGFR T790M status affected treatment decisions, namely to identify a patient eligible for second-line osimeritinib.15 However, now that osimertinib is the SoC first-line therapy for EGFR-mutated NSCLC, EGFR T790M positivity is less relevant because the mechanisms of acquired resistance following progression with osimertinib are different than those following progression on a first-generation EGFR TKI, which we will discuss more below.
Personally, I am uncertain how much value clinical utility testing at disease progression currently offers, although we may find a rare RET fusion, high MET amplification, or another actionable driver to target with off-label targeted therapy rather than transitioning to SoC chemotherapy or a clinical trial.
Edward B. Garon, MD, MS:
I suspect many of our panelists would give a similar answer. I think the role of liquid biopsy is still emerging in the setting of disease progression. A blood draw is quite easy, and liquid biopsy testing has value to identify patients for clinical trials examining various acquired resistance mechanisms to osimertinib. But, to me, it is less clear how practitioners should use the results obtained from liquid biopsy testing outside of clinical trials.
Dr. Piotrowska, would you request a liquid biopsy for a patient with disease progression if a clinical trial is not an option for them, and how would you use the results?
Zofia Piotrowska, MD, MHS:
In a community practice setting with limited access to clinical trials, I would push to consider a tissue biopsy over a liquid biopsy. In advanced nonsquamous NSCLC, a tissue biopsy is required to identify histologic transformation to squamous histology or even to small-cell lung cancer,32-34 which would affect chemotherapy selection. So, in the setting where chemotherapy is the primary second-line option, tissue testing is more likely to uncover an actionable scenario than liquid biopsy testing.
In my practice, because we do have access to clinical trials, we try to perform both liquid-based and tissue-based biomarker testing at progression, but I still try to prioritize tissue testing when possible for the reasons mentioned above. Furthermore, I am not opposed to using an approved targeted therapy off-label if an actionable mutation is identified. For example, there are case reports of off-label use of MET inhibitors in combination with osimertinib when MET amplification is identified as the resistance mechanism.35 Of course, we prefer that to be done in the context of a clinical trial, but if I don’t have a good treatment option for a patient, off-label therapies can be a useful approach.
Edward B. Garon, MD, MS:
Thank you, Dr. Piotrowska. That is a great segue to our next survey question.
Edward B. Garon, MD, MS:
The next survey question asked HCPs about their awareness of mechanisms of resistance to osimertinib. Based on our survey, a majority of HCPs (80%) realize that there are diverse mechanisms of resistance to osimertinib, which contrasts to the predominance of a single resistance mutation, T790M, seen at progression on first-generation or second-generation EGFR TKIs, as discussed above.
Even patients who achieve an exceptional response with a modern EGFR TKI like osimertinib eventually experience disease relapse due to the development of off-target resistance. In more than 70% of cases, the mechanism of resistance to first-line osimertinib remains unknown.33 At this time, we have been able to identify MET amplification (7%), RET and BRAF fusions (4% each), KRAS mutation (4%), EGFR amplification (4%), and EGFR G724S mutation (4%) as some of the potential mechanisms of resistance to first-line osimertinib.
Edward B. Garon, MD, MS:
Off-label use of targeted therapy in the setting of osimertinib resistance has been mentioned by both Dr. Socinski and Dr. Piotrowska. I must admit I have concerns about community oncologists tinkering with off-label drugs or combinations based on just case studies and in the absence of robust clinical trial data.
Dr. Le, how do you counsel community oncologists who contact you for advice when they find a targetable mutation at progression on osimertinib?
Xiuning Le, MD, PhD:
I agree with you that this is a challenging situation, Dr. Garon, but I will recommend TKI therapy or TKI combination therapy to local providers when I think it is warranted. Sometimes this is based on my expertise, but most often, I root my recommendation in clinical data. For example, I have suggested combining a MET inhibitor, such as tepotinib,36 with osimertinib on progression if high MET amplification is detected. As you mentioned above, MET amplification is one of the more common resistance mechanisms to first-line osimertinib therapy, so it is detected quite often, especially by tissue testing. In the phase II ORCHARD biomarker-directed platform trial, interim results for the first arm evaluating osimertinib plus savolitinib in patients with advanced EGFR-mutated NSCLC with MET alterations following first-line osimertinib showed an overall response rate of 41% with the combination,37,51 which makes me comfortable making that recommendation. The other alteration I will make an off-label recommendation for in the setting of osimertinib resistance is the second-site EGFR alteration C797S. For this, I sometimes recommend adding gefitinib or switching to a second-generation EGFR TKI.
Helena A. Yu, MD:
I also appreciate that it is not a good thing to go rogue and make up your own combinations, especially considering that NGS reports are becoming more complicated. There are some data for MET and second-site EGFR alterations, like Dr. Le mentioned, as well as for RET and ALK fusions,33,38 but it is a slippery slope.
Edward B. Garon, MD:
I do appreciate the complexity of this, and for our robust discussion about it. I want to be careful to not give community oncologists unrealistic expectations, because in second opinions, I have seen instances in which outside practitioners have used strategies targeting mutations that are not likely driving the disease—based on my understanding of molecular drivers in these settings—and sometimes adding unnecessary toxicity. This is something I would like to prevent.
Edward B. Garon, MD, MS:
Another interesting question is whether a first-line EGFR TKI should be continued after progression systemically and/or in the CNS. This topic, I believe, highlights how much our previously firm approach to disease management has evolved. There once was a time when many experts in our field believed that someone with advanced NSCLC and an EGFR mutation would never be able to stop an EGFR TKI, even in subsequent lines of therapy following progression.
But then we received the results from the phase III IMPRESS study showing that continuing the EGFR TKI along with chemotherapy after progression had no clear survival benefit. In IMPRESS, gefitinib plus chemotherapy following radiographic progression in patients with EGFR-mutant NSCLC on first-line gefitinib did not prolong the median PFS vs placebo plus chemotherapy (median PFS: 5.4 months in both arms; HR: 0.86; P = .27),39 so the paradigm shifted for the most part to stopping the EGFR TKI. In fact, in the absence of a clinical trial, the current SoC for a patient with progression on EGFR TKI therapy and a significant disease burden and/or symptoms is histology-driven, platinum-based doublet chemotherapy.
However, we are starting to see some of these lines blur again. Dr. Yu, could you tell us a little bit about the scenarios in which someone might continue an osimertinib in the management of patients with EGFR-mutated NSCLC?
Helena A. Yu, MD:
First, I’d like to say that there is 1 scenario in which I think it’s prudent to combine EGFR TKI therapy with chemotherapy—if a patient has systemic progression but stable CNS metastases on osimertinib, then I will continue osimertinib while initiating chemotherapy.
Second, 20% of patients being treated with an EGFR TKI will progress in a solitary lesion, which we call oligoprogression, and a common site of this is in the CNS with brain metastases.40 There are substantial retrospective data showing that for these patients, local therapy, be it with surgery, radiation, ablation, or other measures, followed by continued EGFR TKI therapy, delays the time to new systemic therapy, extending both PFS and OS. This doesn’t apply to all patients, but there is a clear subset of patients in which local therapy along with continuing the EGFR TKI is a viable treatment strategy and can clearly extend the time before a new treatment is required.
Another reasonable treatment strategy is to consider local therapy at minimal residual disease or at best response to the systemic therapy. In a randomized phase II study, patients with metastatic NSCLC receiving SoC systemic therapy—either chemotherapy or an appropriate targeted therapy—who had oligometastatic disease but no progression after 3 months were randomized to receive continued maintenance systemic therapy or local therapy to all sites of disease. 41 The study was closed early by the data safety monitoring board, initially, due to a clear improvement in the time to new lesions with consolidative local therapy; a later update also showed a PFS and OS benefit. Patients with EGFR-mutated lung cancer were included in this study and there is a current ongoing study called the NORTHSTAR study that is recapitulating this treatment strategy in only patients with EGFR-mutated lung cancer receiving first-line osimertinib (NCT03410043). This is a treatment strategy that I think is ready for prime time for the right patient. For patients with minimal disease burden with a good response to initial EGFR TKI therapy, with residual disease amenable to local therapy, I would consider local therapy to all sites of disease followed by continued EGFR inhibition.
Edward B. Garon, MD, MS:
Thank you, Dr. Yu. Those are great examples of how the strict rules around “line of therapy” are breaking down a bit.
Dr. Socinski, I am curious to hear what you think. You have been treating patients with lung cancer for quite some time, along with being involved with many of our paradigm-shifting clinical trials. Do you see the very strict rules around lines of therapy blurring?
Mark A. Socinski, MD:
I do think that the distinct lines of therapy used for sequencing treatment in the past have started to blur. What I learned during my fellowship is very different from how I practice now. For example, there was a time when we would never treat beyond progression. In today’s paradigm, that still may be the right approach with cytotoxic therapy, but with targeted therapies and immunotherapy, I find myself treating beyond progression quite often in this setting. We have moved beyond trying to run out the clock and are now trying to extend the clock as best we can. In a scenario where patients are tolerating a therapy that has clearly benefited them, why change the therapy before you have to? In this era of individualizing and personalizing treatment strategies based on the specific factors of a particular patient, my approach has become much more nuanced. We break down the paradigms and do what we think is right for the patient in settings where we often don’t have a ton of great clinical data to guide us.
Edward B. Garon, MD, MS:
One ongoing question is whether there is any utility in adding immunotherapy to chemotherapy for patients with metastatic EGFR-mutated lung cancers after progression on an EGFR TKI.
Dr. Socinski, you have presented and published data on chemoimmunotherapy in combination with antiangiogenesis inhibitors in this population. How do you typically treat patients who are not found to have an actionable driver after progression on osimertinib? Do you go with chemotherapy alone, chemotherapy plus an immune checkpoint inhibitor, or the quadruple regimen of atezolizumab plus carboplatin/paclitaxel and bevacizumab?
Mark A. Socinski, MD:
In my practice, I recommend either chemotherapy alone, typically carboplatin/pemetrexed, or if a patient is eligible for bevacizumab, the quadruplet regimen of carboplatin, paclitaxel, bevacizumab, and atezolizumab that we evaluated in the IMpower150 trial.
The phase III IMpower150 trial was designed to evaluate whether the addition of an antiangiogenesis agent would enhance outcomes with immunotherapy and chemotherapy in patients with metastatic nonsquamous NSCLC.42,43 This trial was unique among the large immunotherapy trials in lung cancer in that it allowed patients with EGFR mutations or ALK rearrangements after disease progression or intolerance to at least 1 previous line of approved targeted therapy.
In the intention-to-treat wild-type population (n = 1047), which did not include patients with EGFR mutations or ALK alterations, the addition of bevacizumab and atezolizumab to standard platinum-doublet chemotherapy significantly improved PFS (HR: 0.62, 95% CI: 0.52-0.74, P <.001) and OS (HR: 0.80, 95% CI: 0.67-0.95) compared with bevacizumab plus chemotherapy alone.42,43 In an exploratory analysis of the EGFR-mutant subgroup (n = 124 of 1202 patients enrolled), the quadruple regimen also improved OS compared with bevacizumab plus chemotherapy (not estimable vs 18.7 months, respectively; HR: 0.61; 95% CI: 0.29-1.28).44 Improved OS was also observed when looking at only the 58 patients with EGFR-sensitizing mutations (not estimable vs 17.5 months; HR: 0.31; 95% CI: 0.11-0.83).
For patients with EGFR TKI-resistant, EGFR-mutated NSCLC who I do give the quadruple regimen to, the challenge is to get them through the 4 cycles of carboplatin/paclitaxel, because once we discontinue the chemotherapy, it becomes a much more tolerable regimen. For patients who experience toxicities during those 4 cycles, I use aggressive dose reductions to get them through.
Edward B. Garon, MD, MS:
Thank you, Dr. Socinski. I’ll add that recent data from the phase III ORIENT-31 trial (N = 444) is consistent with what you saw in the IMpower150 exploratory analysis for patients with EGFR TKI-resistant, EGFR-mutated NSCLC. The addition of the investigational PD-1 inhibitor sintilimab to chemotherapy plus the bevacizumab biosimilar IBI30 significantly improved PFS vs chemotherapy alone in this setting (HR: 0.464; 95% CI: 0.337-0.639; P <.0001).45
However, is there a role for chemoimmunotherapy in the absence of an antiangiogenic agent in the setting of EGFR-mutated NSCLC, for example, the KEYNOTE-189 regimen of carboplatin, pemetrexed, and pembrolizumab?46 Despite their exclusion from the phase III KEYNOTE 189 trial, anecdotally, I see this combination used in patients with EGFR-mutated advanced NSCLC time and time again when they are referred to me for a second opinion. Dr. Le, what are your thoughts on the use of this regimen for patients with progressive EGFR-mutant NSCLC after EGFR TKI therapy?
Xiuning Le, MD, PhD:
The data suggest that for patients with EGFR-mutated NSCLC, simply adding an anti–PD‑1 agent to chemotherapy without an immunomodulating agent like a VEGF inhibitor is unlikely to provide significant additional benefit. For example, in a small multicenter retrospective analysis of patients with EGFR-mutated NSCLC who had progression following osimertinib, those who received chemotherapy plus immunotherapy had a shorter median OS than patients who received chemotherapy with or without bevacizumab (HR: 2.66; 95% CI: 1.25-5.65; P = .011).47
When I treat patients with EGFR-mutated NSCLC and progression on osimertinib, like Dr. Socinski, I also consider the IMpower150 regimen to be appropriate for a robust patient. If the patient’s performance status is more compromised, I recommend a carboplatin/pemetrexed doublet regimen unless there is evidence of histologic transformation. I also have a discussion with patients about the possibility of continuing osimertinib for potential CNS benefit as demonstrated in the ADAURA trial.1
Edward B. Garon, MD, MS:
It sounds like we are using similar approaches to treat patients following osimertinib progression. I will note that there are studies comparing adding just an anti–PD‑1 agent to chemotherapy vs chemotherapy alone after osimertinib progression in patients with EGFR-mutated NSCLC, such as the phase III KENOTE-789 trial of pembrolizumab plus platinum-based chemotherapy vs chemotherapy alone in patients with advanced NSCLC and L858R or del19 EGFR mutations who progressed after EGFR TKI therapy (NCT03515837). We await more data to see if it changes our mind about using chemoimmunotherapy in this setting.
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