Aaron J. Franke, MD, MS, assistant professor of medicine, Division of Hematology and Oncology, the University of Florida (UF) College of Medicine, associate research leader, Thoracic Cancers Disease Site Group, UF Health Cancer Center, discusses treatment options for patients with uncommon 

 mutations in non–small cell lung cancer (NSCLC).

About 10% of patients with NSCLC will express uncommon 

 mutations, or mutations other than exon 19 deletions or exon 21 L858R point mutations, Franke begins. The most frequent uncommon 

 point mutations are in G719X of exon 18, L861Q in exon 21, S768I in exon 20, and both de novo and acquired exon 20 insertions, Franke states. Approaches to the treatment of these rare 

 mutations are accordingly grouped as either exon 20 insertion mutations or non–exon 20 mutations, Franke explains. Patients with these substitution mutations may benefit from EGFR TKIs.

The retrospective UNICORN/TCOG1901 study (NCT05421936) evaluated real-world outcomes with the third-generation TKI osimertinib (Tagrisso) as a first-line treatment for NSCLC with uncommon 

 mutations. Results from this study were recently published in the 

, and showed that the agent elicited an overall response rate of 61% and a median duration of response of 17.4 months in all cohorts, Franke reports. Further analysis of patients according to mutational status showed that patients with G719X, L861Q, and de novoT790M mutations all responded well to osimertinib. Moreover, patients with compound 

mutations that included both a common and atypical mutation, had better outcomes with osimertinib compared with patients who only expressed uncommon 

Previous data from the phase 2 LUX-Lung 2 (NCT00525148) and phase 3 LUX-Lung 3 (NCT00949650), and LUX-Lung 6 (NCT01121393) trials led to the expanded FDA approval of afatinib (Gilotrif) as a first-line treatment for patients with metastatic NSCLC expressing non-resistant 

 mutations. Afatinib is currently the only drug approved for atypical 

In comparison with these data, findings from the UNICORN trial indicate that osimertinib may bean effective, and potentially more tolerable, addition to the armamentarium, Franke explains. These data also highlight other resistance mutations to target in future therapeutic development, Franke concludes. 

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Aaron J. Franke, MD, MS, discusses treatment options for patients with uncommon EGFR mutations in non–small cell lung cancer.

Dr Franke on Treatment Options for NSCLC Expressing Uncommon EGFR Mutations

In this sixth episode of OncChats: Traveling Through the Lung Cancer Treatment Paradigm, Aaron Franke, MD, discusses the consideration of adverse effects related to treatment with TKIs patients in non–small cell lung cancer.

"[There is something else that] has become very clinically important. I know most clinicians in the field—even those in private practice who are treating 25 different types of tumors in a day—have probably heard the mantra of ‘Wait for the next-generation sequencing [NGS] [results] before treating [patients with] advanced metastatic non–small cell lung cancer.’ However, I think this is a good reminder.

We still see cases [of] heavy smokers, [those] 78 years [of age], veteran patients who you have no ‘suspicion’ of having a driver mutation; their PD-L1 [testing] comes back at 90%, [and] they’re symptomatic so you want to give chemotherapy [and] immunotherapy. You give a reasonable regimen, and then, despite the smoker [status,] despite the age, despite the lack of being the general phenotype, the NGS [results] come back, and he or she has an ALK [mutation], an EGFR [mutation], a ROS1 [fusion], ora RET or MET [alteration].

The problem is now you have an immune checkpoint inhibitor floating around for realistically, weeks to months. You’re kind of slated to deal with that fact in that you want to start a targeted therapy, which most would recommend at this point, but you’re thinking about the synergistic toxicities with these therapies...There is also the bigger unknown space of the ROS1 and the RET drugs, where we don’t know as much about what kind of toxicities lie ahead for patients who have immune checkpoint inhibitors floating around. However, I think we have learned the story from EGFR inhibitors.

I’ve had more than a couple of patients who have been in this scenario. Especially for patients who maybe already have compromised lung function, I will sometimes start them on an older-generation TKI and try to wait out that window before starting, let’s say,osimertinib [Tagrisso,] which again gives you a higher-than-acceptable rate of pneumonitis in the setting of recent checkpoint inhibitors. A patient [who already has] chronic obstructive pulmonary disease—again, they are the smoker, or they are the [patient with the] unexpected EGFR [mutation]—may have very little wiggle room in terms of a window or a margin of error to have a pneumonitis toxicity. In [this] case, they may not be candidates [to receive] any more systemic therapy, despite how efficacious and tolerable it may be. You may not only lose the window, but you may also have blown the gap there.

As such, I think these are very important considerations. Don’t be fooled by the PD-L1 [status]. Always wait on the NGS [testing results]—even for the smokers and the older patients; [they still] make up maybe 15% or up to 20% of [all] oncogene-driven lung cancers, so that’s not an insignificant number."

In this sixth episode of OncChats: Traveling Through the Lung Cancer Treatment Paradigm, Aaron Franke, MD, discusses the consideration of adverse effects related to treatment with TKIs patients in non–small cell lung cancer. 

Traveling Through the Lung Cancer Treatment Paradigm: Taking TKI-Related AEs Into Consideration for NSCLC

In this fifth episode of OncChats: Traveling Through the Lung Cancer Treatment Paradigm, Aaron Franke, MD, of the University of Florida Health, discusses instances where oral etoposide could be utilized for patients with small cell lung cancer (SCLC).

"One alternative in the setting of SCLC is the idea of oral etoposide. This came about as [somewhat] of a pragmatic tool during the [COVID-19] pandemic—especially when I was in Tampa, FL, at the [VA Tampa Health Care]. We had a plethora of new [patients with] SCLC coming in, and we were really trying to limit both travel and clinic exposure to patients as much as we could. This was when we had the alternative dosing [guidance] for immune checkpoint inhibitors come out. This [was also] when we were trying to [use] alternative [approaches for] patients [with multiple myeloma], and really trying to mitigate how much patients had to come into clinic, which at the time was obviously our fear of their biggest risk of exposure to [COVID-19]. [In trying to find ways] to get crafty and limit bad patient outcomes, this was an area where we leveraged probably a less commonly utilized part of the SCLC treatment armamentarium, and that was the use of oral etoposide.

What data do we have to support this? There was a [phase 3] study done in [Japan in patients with] extensive-stage [SCLC] where they looked at irinotecan [plus carboplatin] vs etoposide and carboplatin, and irinotecan seemed to [result in] a little bit better of an outcome. Now, granted, they were using oral etoposide in this, but they also were using carboplatin at an area under the curve of 4. I think those 2 combined is where you saw a little bit more of a slight prolongation in overall survival and benefit of irinotecan, [at] 8.5 months vs 7.1 months. However, I don't think that's the bigger story to take away from it.

You know, there are data supporting oral etoposide. [Published] around 2004, this was a study that mostly looked at patients getting cisplatin with chemoradiation, and [they] got oral etoposide. I still think about this [for use] in patients who travel very far, where the logistics of traveling for 3 days in a row for chemotherapy is still an issue. I will sometimes offer patients the day 2 and 3 as oral etoposide. Now, remember, the dose is twice as much, so if you’re giving 80 mg/m2 intravenously [IV], you’re going to give 160 mg orally. Also, if this patient weighs over 70 kg to 80 kg, it’s usually going to be a split dosing based on the total mg per day. So, there are some dosing nuances to think about there, and again, giving patients prophylactic antiemetics so they do not throw up their pills [is another thing to remember].

One thing I counsel patients on, who opt for this therapy or [for whom] I find this [approach] to be pragmatically an easier fit than traveling 3 days in a row to the clinic, is the psychological burden that sometimes is put on [them] when they are in charge of their [treatment]. When I give all 3 days IV, I know that they’re getting the drug [and] they’re getting the full dose; there’s no, ‘if,’‘ands,’ or ‘buts’ about it. Giving them the luxury of [being able to take] it at home for their convenience also gives them the responsibility that they need to take their drug, they cannot throw it up, and they need to take it at a reasonable time, the way it's supposed to be taken—with or without food, with or without other drugs. Sometimes that extra anxiety really puts a lot [of pressure] on them. If they missed their dose, they lose their pill, they can’t get it from the pharmacy, they throw it up, or anything else happens, they really have a lot of extra anxiety [because] they may be compromising their own outcomes.

I try not to put any unnecessary angst on a patient who’s already going through a very anxiety-prone scenario. I [explain all] this to the patient up front, that this responsibility and this extra pressure is there. [I remind them] that we can obviously mitigate [this anxiety] by giving [the treatment] through the IV if traveling is not a concern; I think [this] is something to consider [when] traveling the 3 days really is a treatment-limiting factor in their ongoing treatment [journey]. If they can’t get treatment locally…, consider day 2 and 3 oral therapies with these nuances in mind."

Check back next Wednesday for the final episode in this series.

 In this fifth episode of OncChats: Traveling Through the Lung Cancer Treatment Paradigm, Aaron Franke, MD, discusses instances where oral etoposide could be utilized for patients with small cell lung cancer. 

Traveling Through the Lung Cancer Treatment Paradigm: Oral Etoposide

In this fourth episode of OncChats: Traveling Through the Lung Cancer Treatment Paradigm, Aaron Franke, MD, of University of Florida Health, discusses the management of immune-related adverse effects (AEs) and the goal of mitigating steroid use for patients with lung cancer.

"One of the points of contingency is the use of corticosteroids in patients [with lung cancer] receiving immune checkpoint inhibitors. I know we have accumulating data that, to date, show there does not seem to be a noticeable detrimental effect in terms of the treatment efficacy in patients receiving steroids.

These patients, especially with dermatitis and some of these endocrinopathies, who have mild to moderate immune therapy–related AEs tend to have better responses and maybe better outcomes as long as there’s not a detrimental mortality to the AEs [themselves], like with pneumonitis or colitis. So, whether these patients who receive steroids or not, [whether] their survival is not pushed over or influenced by the steroids may be a surrogate for their biological activity to begin with. We know that most of these studies did not allow patients who were on chronic steroids above 10 mg daily equivalent of prednisone. How much data [do] we have to really parse through to say that patients did not have a detriment in the setting of receiving corticosteroids?

I think one part of this we're forgetting is that the chemotherapy regimens themselves, the paclitaxel without the [nab-paclitaxel (Abraxane)] version of it, or even pemetrexed, where we give 3 days of over 8 mg twice daily of dexamethasone, which again, is not an insignificant dose of prednisone to give for 3 days. I have adopted from institutional studies, where they had given a single dose of steroids, dexamethasone 12 to 16 mg on the day of chemotherapy. Now, I think there about 3 retrospective studies where they looked at patients who got the 3 days of dexamethasone vs the single day of dexamethasone for the pemetrexed chemotherapy premedication at least, and the rate of rash was about the same; it was less than 4% or 5%. Again, I really don't see much in the way of pemetrexed [and] rash. I do believe that giving less total steroid dosing, both duration and total dosing, is something that in my mind helps protect the patient a little bit against upregulating this T-cell immunosuppressive environment where we're upregulating the T regs and downregulating the cytotoxic T cells.

The other end of this story is, when we saw the upregulation of interleukin-6 inhibitors and tocilizumab [Actemra] used as COVID-19 protocols during 2020 and 2021 in patients who were on immunotherapy, or those who were having immunotherapy[-related] AEs that ended up getting tocilizumab as a byproduct of having COVID, or even those treated in the setting of having an immune-related AE, there seems to be a synergistic or better outcome in terms of their oncologic end points vs steroids. You can look at retrospective institutional studies and gather that despite the lack of data in the prospective phase 3 studies, there is a story to be told where we are not doing good biologically by having the need for steroids or maybe an unnecessary amount of corticosteroids in the regimen for patients who are on immunotherapies.

Going forward, [we are] trying to treat immune-related AEs and thinking about things as small as chemotherapy protocols with steroids involved and trying to mitigate as much use of that as we can. We're going to see the story play out. Even if it's only of mild significance, I think it is something that is biologically where I am in the school of thought that we are doing a harm to what we're trying to upregulate in the tumor milieu in the microenvironment.

I'm looking forward to alternative immune-related AE treatment protocols, as well as alternative chemotherapy premedications, where we can mitigate or eliminate steroid use."

Check back next Wednesday for the next episode in this series.

In this fourth episode of OncChats: Traveling Through the Lung Cancer Treatment Paradigm, Aaron Franke, MD, discusses the management of immune-related adverse effects and the goal of mitigating steroid use for patients with lung cancer. 

Traveling Through the Lung Cancer Treatment Paradigm: Managing irAEs With Corticosteroids

In this third episode of OncChats: Traveling Through the Lung Cancer Treatment Paradigm, Aaron Franke, MD, of the University of Florida Health, discusses the expanding role of neoadjuvant therapy in non–small cell lung cancer (NSCLC) and efforts to better identify patients who can benefit from curative-intent treatment.

"One of the exciting recent evolutions [regarding] new drug approvals in a shifting paradigm that has really caught the eye and excitability of the masses, has been the incorporation of neoadjuvant therapy for the resectable NSCLC population.

In particular, an immune checkpoint inhibitor with chemotherapy in the up-front setting [is being used] to deliver higher compliance and improve overall outcomes in terms of event-free survival and ultimately, overall survival. [It is important to] remember that about 12% of newly diagnosed cancers and 20% of this mortality, is really related to the nonmetastatic setting, where about one-third of our patients present.

Despite curative-intent [approaches] with surgery and chemotherapy, plus or minus radiation, these [approaches] are not a walk in the park to go through; they still come with pretty high relapse rates. The disease-free survival really drops down to about 40% once you get closer to stage III [disease]. Even [with those who have] stage IB and II [disease, with rates of] 65% to 70%, you're still talking more than one-third of patients relapsing from their disease, almost inevitably with locally advanced or metastatic incurable disease at that point. Historically, [these patients have had] pretty poor outcomes. Again, we're talking before oncogene-driven targeted therapies and immunotherapies for the advanced space, but nonetheless, trying to improve the local setting, the curative setting to really ensure a cure is a cure when we say curative intent, or at least trying to bolster and enrich that population, should be a definite goal. We've seen the metastatic benefits of immunotherapy shift down from stage IV to then the stage III in the locally advanced space, and now, we've seen it in the adjuvant and neoadjuvant space.

Some of the caveats, just to keep in mind, is that this requires a multidisciplinary meeting of the minds, and I know that in the community, that is sometimes a little tougher if everyone is at a different institution—the surgeon, the radiation, the medical oncologist, and the pathologist, etc. It takes coordination to at least get a referral to a cancer center or local academic center to get the opinion of [if the] patient [is] a good candidate up front based on their tumor profile or molecular profile, based on the tumor characteristics. What nodal stages is it in? How likely is [the] patient to get their therapy on time [and] get to surgery? Again, we’re trying to give efficacious therapy up front that is mildly guided by biomarkers, but ultimately, histology and a small smidgen of tumor information that we have at the time. Mostly, [we’re using] clinical information from the patient, so their history and their tumor staging, to try to give the best compliance we can to a therapy to ultimately have the best pathologic outcome that will guide us hopefully as a surrogate for overall clinical outcomes.

We’re looking at pathologic complete response and clearance of circulating tumor DNA as another side product to ultimately try to decide who are the patients that benefited up front. If they did not, what we can do out back for them is still a question that remains and will be a discussion for another talk. However, right now, a clinical trial is probably [the] best option [for those patients]."

 In this third episode of OncChats: Traveling Through the Lung Cancer Treatment Paradigm, Aaron Franke, MD, discusses the expanding role of neoadjuvant therapy in non–small cell lung cancer and efforts to better identify patients who can benefit from curative-intent treatment. 

Traveling Through the Lung Cancer Treatment Paradigm: Taking Advantage of Neoadjuvant Therapy

In this second episode of OncChats: Traveling Through the Lung Cancer Treatment Paradigm, Aaron Franke, MD, of the University of Florida Health, discusses the need for additional circulating biomarkers beyond PD-L1 in non–small cell lung cancer (NSCLC).

"Another topic that’s gaining a lot of momentum, but still has a lot of unanswered questions and an unmet need is the biomarker guidance in non–small cell lung cancer treatment. This is outside of the exciting oncogene explosion where we now have, I believe, 11 actionable, targetable mutations, as well as a smattering, a handful of prognostic mutations that are helping [move the needle] as they gain more and more data, [such as] STK11, KEAP1, KRAS, and [others]. However,...outside of a research initiative...you must remember that PD-L1, despite all its caveats and downfalls, really stands to be the most studied and only validated recommended biomarker to guide immune checkpoint inhibitor clinical decision making in NSCLC.

I won't get into tumor mutational burden in this segment, but really, PD-L1 is the one where guidelines really have the dichotomy and the algorithm kind of grouped together based on this, outside of an oncogene expression. However, while PD-L1 tumor cell expression remains a unique and uncontested immune biomarker and clinical tool, its prognostic significance remains more unclear than most people would think. There are considerable gaps in our knowledge that remain, and a relatively a lack of consensus on how to best harmonize PD-L1 testing and mitigate or at least control for the multitude of clinical pitfalls we see with PD-L1 testing. More importantly, the biologic and clinical implications of such an imperfect immunotherapy biomarker [are not fully understood].

Notwithstanding the practical issues, I do want to emphasize that PD-L1 is not in the same league as other much more informative biomarkers like EGFR and ALK. [The latter] biomarkers, when present or absent, have an inherent value; they reliably tell the clinician to predict a therapeutic benefit in an overwhelming majority of patients or to predict no benefit in the absence of such a mutation or a fusion. Conversely, when you look at PD-L1, this is a continuous variable; it’s more of an enriching biomarker. If you raise the threshold of the PD-L1 cutoff, you get a higher response rate in terms of the patients who are treated; if you scale it down, [with] the defined cutoff on the lower end, you're going to decrease the proportion of patients who are receiving the interventional treatment...

Although these are both valuable objectives to consider, let’s say when designing trials or even thinking about your clinic patients as you’re going to expand the eligibility pool and ostensibly maximize the magnitude of therapeutic benefit, they're diametrically opposed intentions. As such, attempting to achieve a kind of bidirectional satisfaction here can further complicate an already clinically complex situation, and one could argue maybe challenge some bioethical, philosophical principles. We [should] remember that the reliability, the reproducibility, is very limited by the spatial and temporal heterogeneity. Treatment obviously has a dynamic regulation and susceptibility to PD-L1 expression where you are biopsying the primary vs the metastatic site, the nodal vs the primary mass, pre [or] post treatment. We even see huge discrepancies between preoperative biopsies and post–surgical resection specimens when we’re talking about the percentage of PD-L1 high and intermediate when there can be anywhere from a 20% to 45% discrepancy in, let's say, a PD-L1–high expression. This has treatment implications.

We now have neoadjuvant and adjuvant immunotherapies that come into play based on, again, this PD-L1 biomarker. I think the overall goal here is not to [take away from] all the good that PD-L1 has done or take back all of the trials that are obviously rooted and predicated on...splitting up groups into certain treatment subsets, most of them in a post-hoc fashion, but I think it's more to open the door and try to say we need to move forward and try to evolve with newer, smarter biomarkers, circulating biomarkers. [We need to] really try to elevate this field of where we’re going, so we can better enrich for the patient populations benefiting [from certain therapies] and limit the patients who aren’t benefiting from therapies that are not without significant adverse effects in some of these patients.

That’s something we need to keep in mind moving forward. That’s an unmet need that we’re all striving to get involved with, from a research standpoint, because I think it’s very, very translatable to the clinical realm of lung cancer treatment."

In this second episode of OncChats: Traveling Through the Lung Cancer Treatment Paradigm, Aaron Franke, MD, discusses the need for additional circulating biomarkers beyond PD-L1 in non–small cell lung cancer.

Traveling Through the Lung Cancer Treatment Paradigm: Biomarker Guidance in NSCLC

In this first episode of OncChats: Traveling Through the Lung Cancer Treatment Paradigm, Aaron Franke, MD, of the University of Florida Health, discusses the exploration of cellular therapies in non–small cell lung cancer (NSCLC).

"I just wanted to briefly bring up the segue of adoptive cellular therapies from the hematological space, where they kind of made their boom about 7 years ago, into the solid tumor space—specifically, NSCLC.

[Although] immune checkpoint inhibitors have obviously revolutionized the advanced and metastatic settings of NSCLC, and now have even made their way into the surgically curable setting in terms of improving patient outcomes, the majority of our patients either do not benefit or gain the long-term benefit. Eventually, [these patients] relapse and succumb to their disease, despite up-front good therapies and maybe about one-third of our patients getting these long-lasting responses. After immunotherapies have failed—and the patient has not failed, the treatment has failed, we must remember the nomenclature is important here when we’re talking to patients—there are very little data for post-immunotherapy drugs and what regimens are efficacious. However, even if we go back to the single-agent chemotherapies, docetaxel or ramucirumab [Cymraza] options, post immunotherapy or not, these treatments have very marginal efficacy. Although it’s still statistically significant, how clinically beneficial it is and how long lasting it is, is again measured on the order of months.

As such, trying to find something to reinvigorate the immune system or, I should say, satiate the T-cell exhaustion, [to] overcome the immunotherapy checkpoint inhibitor resistance that's either acquired or inherent to the tumor, is something that adoptive cell therapies are looking [to address]. These [products] range from tumor-infiltrating lymphocytes [TILs], T-cell receptor engineering, CAR T, and [other approaches]. Generally, this is just a personalized treatment strategy that is going to isolate a patient's own immune cells; [it is] followed by an ex vivo expansion and re-infusion in the setting of TIL therapy, [for example]. The rationale for this is really trying to turn what we call ‘cold’ tumors ‘hot’ by essentially maximizing the host antitumor defenses in response and upregulating the antigenic proliferation or response to the tumor-related proteins in the lung cancer that was otherwise deemed cold and nonresponsive based on the microenvironment.

We saw the first [phase 1] study [NCT03215810] on [TIL therapy], from Ben Creelan, MD, of Moffitt Cancer Center, and the early phase 1/2 data, and if you look at the overall outcomes...you see an objective response rate in [3 of 13] of patients, with [2] of these patients having a complete response and a disease control rate of about 65%. Again, [this is being seen] in patients who have already progressed on at least 1 line of therapy, including an immune checkpoint inhibitor. In the absence of other cytotoxics and immune checkpoint inhibitors that can overcome this resistance, looking at patients who may be that may be eligible for this kind of therapy, despite the nuances of it, I would say that this is a clinically relevant, very attractive and encouraging target [that is] reinvigorating a once-exhausted immune system for those patients who progress on our first-line therapies."

In this first episode of OncChats: Traveling Through the Lung Cancer Treatment Paradigm, Aaron Franke, MD, discusses the exploration of cellular therapies in non–small cell lung cancer.

Aaron Franke, MD

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