Chemotherapy’s Role Reevaluated in Early-Stage EGFR+ NSCLC

Edward S. Kim, MD, MBA (Moderator)
Physician-in-Chief, City of Hope Orange County
Vice Physician-in-Chief, City of Hope National Medical Center
Newport Beach, CA

DISCUSSION QUESTIONS

• What concerns do you have when using various adjuvant therapies for non–small cell lung cancer (NSCLC)?

RAYMOND LOBINS, DO: Looking at the guidelines for adjuvant chemotherapy, they all say cisplatin to this day.¹ So when a patient comes in who is not eligible for cisplatin, you can give them atezolizumab [Tecentriq], even though it wasn't done in IMpower010 [NCT02486718]. Do you give him a carboplatin-based adjuvant chemotherapy so you can get into atezolizumab? Or do you follow the guidelines?

EDWARD KIM, MD: I try to give cisplatin and we even give a reduced dose of cisplatin. If the patient cannot tolerate cisplatin due to kidney disease, etc, we don't have the data right now that giving adjuvant atezolizumab is enough. It might be, but don't have that answer and it is a commitment to give it to someone like that. Getting immunotherapy can also cause some kidney issues as well. So, we want to be cautious of that.

I remember an exception years ago—maybe over a decade ago. I gave carboplatin instead of cisplatin to a patient because he had a stage IIIA tumor, so he had pretty high risk. He was in his mid or late 80s as far as age but…he looked like he was 55 years old, even though he was chronologically very old. I did it because he had late-stage disease.

He was ‘all in’. He wanted to do everything he could because he [wanted to] live to over 100. And he lived for a long time, I will say. That was the only time I did that.

I was never a believer in carboplatin in this situation otherwise, and part of that is because I also treat head and neck cancer and we know that carboplatin doesn't work as well [as cisplatin] with radio-sensitization, for instance.² So we would always say what's the problem? We give 100 mg/m² of cisplatin all the time to patients with head and neck cancer with radiotherapy. Why can't you do that in lung cancer?

I think trying to stick with cisplatin is always better from that standpoint, but we're still learning. The fact that we have atezolizumab in conjunction [with cisplatin], we have osimertinib [Tagrisso] in conjunction [with it, and] any question that comes up is a very related one. Do you even need to give chemotherapy if you have a driver mutation present? That's come up as well. We don't have an answer yet.

We know that no matter how intentionally good and altruistic you're trying to treat a patient—you could treat them by the book—the disease still can act badly, [even when] you do everything right. You want to be careful with deviations because you might have that patient where their disease is going to act badly.

DISCUSSION QUESTION

• How do you discuss the option for adjuvant osimertinib with your patients? ​

KEVIN PALKA, MD: Dr Kim, do you think it's necessary to give adjuvant chemotherapy to these patients? It almost seems like it's not critical. These patients with stage IIIA disease are doing great on just osimertinib and they don't need the chemotherapy and its toxicity.³

KIM: I think that's what we have to learn next, especially because we finally have identified biomarkers that are so specific and so precise. And we have them with multiple different therapies. I would not consider it in the same [way] as KRAS right now.

But when you have ALK and ROS1 and some of these [biomarkers] where you're getting huge response rates and we're seeing data like [we saw in the ADAURA trial; NCT02511106], I think it does beg the question, is it similar to the metastatic setting, where we were not giving chemotherapy upfront, and these drugs have largely replaced that in the first-line setting.¹ It's a valid question to ask.

I've been asked the question directly, not necessarily, “Would you skip chemotherapy,” but “If you couldn't give chemotherapy and they're EGFR-positive, would you still treat them osimertinib?” My answer [to that] is yes, I would like to. If they were chemotherapy-ineligible, I would try to fight to put them on osimertinib. Would I skip the chemotherapy right now and go to osimertinib? The answer is no, but I think that's the direction it'll eventually go.

BENJAMIN GEORGE, MD: There is a [group] who do progress on these EGFR inhibitors. After that, do you retest them? What does that field look like?

KIM: The 2 [worst] areas right now are EGFR-mutant refractory and immunotherapy refractory. They're the new areas we're exploring…and there are a lot of [regimens] under investigation. So, anytime somebody progresses or recurs, I absolutely want to retest them. So, if I can get a tissue biopsy, I do that.

If for some reason it's too dangerous getting a tissue biopsy, we do have blood-based biomarker testing. But I'll remind you that in a study that was reported in 2011 by the Harvard investigators when they followed people in the metastatic setting with EGFR mutations who treated on tyrosine kinase inhibitors [TKIs], there was about a 15% histologic transformation rate to small cell lung cancer [SCLC].⁴ You’re not going to find that in the blood, so test tissue if you can. Keep it in mind that you can have histologic transformation. If there's nothing [unexpected] on the biopsy and it's just garden-variety NSCLC that's progressing, you can't give them immunotherapy [after osimertinib], so I'd go to a chemotherapy treatment.

At least for an EGFR TKI, if there's a clinical trial that's looking at patients who are refractory to EGFR inhibitors, then that's also the No. 1 choice. For immunotherapy, it’s the same; you're trying to look and see if there's a combination or a biomarker or something. Those patients could have KRAS and it's not mutually exclusive to treat them so that's possible as well.

But these 2 areas are the new frontiers. Hopefully in 2 to 3 years, we'll have answers for those populations the way science is moving right now. Remember, 20 years ago, we had no hope that anything was going to change and it's gratifying to see all this.

IKE ONWERE, MD: In the patients [who were EGFR positive and their disease has] transformed to SCLC, do you typically give them carboplatin-etoposide and immunotherapy or do you give them chemotherapy only?

KIM: I would think that when you rebiopsy them and the EGFR mutation was gone and it [has transformed into] SCLC, that immunotherapy is on the table. Rebiopsying as well as the reclassification of the biomarkers is important. If the patient doesn’t have an EGFR mutation, then I think it's fair. I have not had a patient where I've had to make that decision, but I'm just telling you what my thought process would be. But even if you didn't, I don't think you'd be at fault for giving a platinum-etoposide combination.

_References:

_{1. NCCN. Clinical practice guidelines in oncology. Non–small cell lung cancer, version 1.2023. Accessed January 23, 2023. https://bit.ly/3GYx3Pz}

_{2. NCCN. Clinical practice guidelines in oncology. Head and neck cancers, version 1.2023. Accessed January 23, 2023. https://bit.ly/3iVV5CT}

_{3. Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071}

_{4. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26. doi:10.1126/scitranslmed.3002003}