Impact of Molecular Testing on First-Line Treatment Decisions in NSCLC

During an OncLive Peer Exchange video roundtable discussion held in the spring of 2013, the following five lung cancer experts discussed recent advances and current issues surrounding the treatment of non-small cell lung cancer (NSCLC): David R. Gandara, MD, director of the Thoracic Oncology Program at University of California Davis Cancer Center; Corey J. Langer, MD, director of Thoracic Oncology at Abramson Cancer Center of the University of Pennsylvania; Alan B. Sandler, MD, principal medical director at Genentech (formerly at Oregon Health & Science University); Mark A. Socinski, MD, director of the Lung Cancer Section at University of Pittsburgh; and Anne S. Tsao, MD, director of the Thoracic Chemo-Radiation Program at The University of Texas MD Anderson Cancer Center. In part one of this series, the faculty discussed several issues surrounding the impact of molecular testing on upfront treatment decisions for patients with advanced NSCLC.

David R. Gandara, MD

Professor of Medicine Division of Hematology and Oncology Director, Thoracic Oncology Program, Associate Director, Clinical Research, UC Davis Cancer Center Sacramento, CA

Concurrent or Sequential Molecular Testing?

Dr Gandara: Corey, I know you raised the issue about concurrent versus sequential testing. Our thinking is evolving for symptomatic patients with stage IV disease, because if you test first for EGFR mutation and then wait for the results, and then have to test for EML4-ALK, etc, a lot of time can go by. How do you decide on an individual patient basis whether you will test concurrently or sequentially?

Dr Langer: We routinely perform molecular testing concurrently for at least EGFR and EML4-ALK. The big issue is the timing. We ideally like to get these results within 1 to 2 work weeks. If patients are highly symptomatic and very ill with a declining performance status and the test results are not back yet, I’ll start them on chemotherapy. For these patients, we don’t really have the luxury of waiting.

Stay the Course With Chemotherapy or Switch to EGFR Inhibition?

Dr Langer: The big dilemma, of course, is what to do after these patients have received a cycle or two of chemotherapy and their disease has stabilized or improved, and the test results are positive for EGFR mutation. Should we switch to erlotinib at that point or should we see them through the course of chemotherapy and then perhaps use erlotinib as a maintenance approach or even integrate it later on in the second-line setting? I don’t think we have a firm grasp on the optimal approach.

Dr Gandara: What would you do?

Dr Langer: If patients are doing well on chemotherapy, I will actually maintain them on chemotherapy for 4 to 6 cycles and then go on to maintenance therapy. Depending on the nature of their response, how symptomatic they were at presentation, and how well they’re tolerating the chemotherapy, I will choose either switch maintenance (use of an agent for maintenance that was not used in the first-line setting) or continuation maintenance (use of a component of the first-line agents for maintenance). If they’ve had a tough time with the chemotherapy, I’ll typically go on to erlotinib maintenance. Certainly, the SATURN trial showed a major progression-free survival (PFS) advantage for erlotinib maintenance in patients with EGFR-mutated disease (see NSCLC trials).^1,2 That hazard ratio is down around 0.1,2 which is really one of the most striking results I’ve ever seen. Therefore, deciding how to treat patients in this situation is a big dilemma, but it’s a better dilemma to have than we have had in the past (ie, before the advent of erlotinib, bevacizumab, pemetrexed, crizotinib, and afatinib). Dr Sandler:I would echo that. I am a firm believer that you should complete the chemotherapy evaluation, at least to 2 cycles. The response rate for EGFR inhibition in EGFR-mutated disease is approximately 70%,³ but if your patient responds, that’s 100% for that patient and, prognostically, patients with EGFR-mutated disease do better with chemotherapy than those with EGFR-wild-type disease (see NSCLC trials sidebar— IPASS).⁴ So, I get those 2 cycles in and then if they’re doing well, I continue as I would without knowing their EGFR mutation status and then I would make that same assessment you did, Corey, and would probably use erlotinib as maintenance.

Important NSCLC Trials of EGFR Inhibitors

SATURN trial:A phase III trial that examined the addition of maintenance erlotinib after first-line chemotherapy with a platinum doublet in patients with advanced NSCLC. Median progression-free survival (PFS) was significantly but modestly longer with erlotinib than with placebo (12.3 weeks vs 11.1 weeks; hazard ratio [HR] = 0.71; P < .0001).1 However, in the EGFR mutation-positive subgroup, erlotinib had a profound predictive effect on PFS compared with placebo (HR = 0.10; P < .001).²

IPASS trial: A phase III trial that compared gefitinib to carboplatin/paclitaxel in previously untreated patients in East Asia with advanced adenocarcinoma. The gefitinib group showed a PFS advantage compared with the chemotherapy group (HR = 0.74; P < .001).⁴ Among the patients with EGFR-mutated disease, PFS was significantly longer for gefitinib compared with chemotherapy (HR = 0.48; P < .001).⁴ Compared with EGFR-wild-type disease, those patients with EGFR-mutated disease had a higher response rate to chemotherapy (47.3% vs 23.5%).⁴

EURTAC trial: A phase III trial that compared first-line erlotinib to doublet chemotherapy in patients with advanced EGFR-mutated (exon 19 or exon 21) NSCLC. Median PFS was 9.7 months in the erlotinib group, compared with 5.2 months in the chemotherapy group (HR = 0.37; P < .0001).⁵ First-line erlotinib produced a grade 1/2 rash in 67% of patients and grade 3 rash in 13% of patients.⁵

LUX-Lung 3 trial: A phase III trial that compared afatinib with cisplatin/pemetrexed in patients with advanced EGFR-mutated adenocarcinoma. Based on its PFS advantage over cisplatin/pemetrexed (HR = 0.58; P = .0004),¹³ afatinib recently earned FDA approval for patients with EGFR-mutated disease. When only patients with the common exon 19 and 21 mutations were examined, the HR was 0.47.¹³

Dr Langer: It’s intriguing. If you look at survival from the EURTAC trial in the setting of EGFR mutation, whether erlotinib was used first- or second-line after chemotherapy failed, the survival was essentially the same (see NSCLC trials sidebar).⁵ This echos prior data from Rosell et al published in NEJM, where survival seemed to be identical whether EGFR TKIs were given first- or second-line.

Dr Socinski: And I think part of the art of managing advanced NSCLC now is not abandoning prematurely therapies that are working. For a patient with a very nice symptomatic, radiographic response to chemotherapy, I would have no problem continuing that treatment, followed by some form of maintenance. Then, as shown by the EURTAC results,⁵ you have a very good second-line treatment—erlotinib—for that particular patient. So, I don’t think getting an EGFR-positive test result necessarily mandates that you switch to erlotinib. Remember, erlotinib is a convenient drug, but it has its share of toxicities (see NSCLC trials sidebar—EURTAC).⁵ Dr Langer: I agree, it can be quite toxic. I just saw a patient yesterday who had a grade 3 rash. He’s thrilled because his disease is essentially in complete remission, but, to be frank, he’s had a bit more toxicity on erlotinib than he had on prior chemotherapy.

Dr Tsao: If I get test results showing the patient has an exon 19 deletion, I am more likely to push to get them onto an EGFR TKI because we know that those patients are probably a little bit more sensitive to the EGFR TKIs.^6-8 The ones who have the rare EGFR mutations, and sometimes those with the more common L858R point mutation, I will let them ride out the chemotherapy for 4 to 6 cycles and then switch them over to maintenance erlotinib. Dr Langer: I haven’t really made distinctions based on the nature of the two actionable activating mutations in exon 19 and 21 (see EGFR mutations).

Specific EGFR Mutations in NSCLC Tumors

T790M mutation:Point mutation in the tyrosine kinase domain, in which threonine is replaced by methionine at codon 790. This mutation is believed to be acquired through selective pressure during treatment with erlotinib.⁹ Thus, patients can have dual mutations: their endogenous EGFR mutation and the acquired T790M mutation.

Exon 19 mutation: In-frame exon 19 deletions that usually include deletions of leucine-747 to glutamic acid-749.⁹ These mutations account for ~45% of all EGFR mutations.⁹

Exon 21 mutation: Point mutation in exon 21, most frequently in which leucine is replaced by arginine at codon 858 (L858R).⁹ Exon 21 mutations account for ~45% of all EGFR mutations.⁹ Studies have shown that patients with exon 19 mutations have higher response rates,^6-8 improved PFS,¹¹ and improved OS7,11 compared with patients with exon 21 mutations.

Uncommon mutations:The remaining 10% of EGFR mutations are missense mutations or in-frame duplications and/or insertions in exon 20.⁹ In a clinical study of 34 patients with EGFR mutations, the 5 patients with exon 20 mutations failed to achieve a response to gefitinib, despite a response rate in the overall population of 55%.¹²

Dr Socinski: You know, I might feel exactly the opposite, Anne. If the patient has an exon 19 deletion, which means they are quite sensitive to EGFR inhibition,^6-9 then I might choose to let them ride out the chemotherapy or maintenance therapy, perhaps including bevacizumab, and then I would think about using erlotinib, knowing that they’re going to be quite sensitive. I don’t think we have consensus on this management issue yet.

Dr Gandara: This situation perfectly illustrates the value of this educational series—we’re raising a lot of questions today that, in reality, have no right or wrong answers. We have an expert panel and we get to have different opinions.

I’ll throw in my own two cents: Our published data suggests that patients with EGFR mutations have very low DNA repair capacity,¹⁰ which suggests that they should respond better to platinum-based chemotherapy. Our data mimics the data from Mass General. And, interestingly, it is the exon 19 deletion tumors, which are most sensitive to chemotherapy, that have the lowest ERCC1 expression.¹⁰ So, I actually feel comfortable about finishing up the chemotherapy for those patients with EGFR-mutated disease, but, again, there’s no right or wrong answer here.

Is EGFR Mutation Testing Prior to Erlotinib Necessary?

Dr Gandara: Well, I have a case I’d like to present to Anne, and I think the answer here will be obvious, but it’s a valuable take-home message. I’ll give you the case of a young woman, 39 years old, who’s never smoked, and she has now been diagnosed with stage IV adenocarcinoma of the lung. Would you, in 2013, offer this patient erlotinib without molecular testing?

Dr Tsao: Absolutely not. The IPASS data indicate that you can actually cause some harm to an EGFR-wild-type patient if you treat them with an EGFR inhibitor (see NSCLC trials sidebar).4 So, it’s very critical to test these patients before you make that first-line decision.

Dr Gandara: I’m sure a lot of our audience is familiar with the IPASS study by Tony Mok,⁴ but I just want to emphasize the trial population, because these were all poster children for EGFR TKIs. They were all patients from East Asia. Nearly all had adenocarcinoma. Nearly 80% of the patients were female and 94% of the patients had never smoked.⁴ So, if you had to pick a population for EGFR inhibition based on the phenotype, this would be it, and yet if they didn’t have that EGFR mutation in their cancer, they did much better with standard chemotherapy.

Dr Langer: Approximately 40% of that population did not have the mutation,⁴ which frankly I was surprised about. I thought it would be a smaller percentage. So, getting the mutation testing, even in a phenotypically favored patient, is absolutely crucial.

Dr Socinski: That’s why I think the IPASS trial is a game changer. I think it’s probably the most important trial we’ve seen in lung cancer because it really defined lung cancer as having a genotypic abnormality, and it ushered in this era of molecular genetics. This is critical because you can no longer sit in your office, simply look at your patients, and decide to give them erlotinib. And you wondered why some of these people didn’t do very well on erlotinib and whether they would have done better with other approaches.

Dr Sandler: These data also illustrate that not only identifying those patients who should be treated with something, but identifying a population that should not be treated with something can be just as important.

Are All EGFR Mutations Created Equal?

Dr Tsao: I would also add that I think it’s going to matter, and not just prognostically, what the specific mutation is. For instance, a patient might have a dual mutation, including the T790M mutation (see EGFR mutations sidebar). It’s very rare, but if they have that, they are not going to respond to the EGFR TKIs.⁹ This example emphasizes that not only do you have to get the biopsy and find out what the mutation is, but you have to know the subtype of the mutation.

Dr Langer: In the IPASS trial, there were approximately 30% of patients with EGFR-mutated disease receiving gefitinib who didn’t respond,⁴ so one wonders if that might have been due to this type of dual mutation.

Dr Socinski: Yes, I think it’s an important point because, although we speak broadly about EGFR mutations, there’s actually a spectrum of the mutations. There are the common ones—exon 19 mutations are prognostically better than exon 21 mutations— but then there are the uncommon ones, and for many of them, we don’t really understand what role EGFR TKIs play.

Dr Gandara: Well, Mark, maybe you could just briefly expand on that topic, because perhaps some of our audience hasn’t yet made that distinction. The two most common EGFR mutations are the exon 19 deletions and the L858R point mutation in exon 21 (see EGFR mutations sidebar). What do the studies show?

Dr Socinski: About 90% of the patients that have a mutation will have one of these exon 19 or 21 mutations—they’re almost a 50/50 split.9 Between the two, the exon 19 mutations do better with regard to response and PFS (see EGFR mutations sidebar). ^6-8,11 Anne’s made that point a couple of times, and I agree that you need to think differently about exon 19 and 21 mutations in your clinical decision making, at least to some extent. In my practice, when I get the result back that a patient has an exon 19 mutation, I get a little excited. If it’s an exon 21 mutation, I think, “Hmm, I wish it were 19.” So, you have that distinction between the two most common mutations.

The other 10% of patients have an uncommon mutation, but this is really a spectrum of mutations. These patients tend not to do as well (see EGFR mutations sidebar).¹² I recently had a patient this week who had a KRAS mutation but had an exon 21 EGFR mutation that I had never heard of before. I don’t quite know what to make of this yet, but I need to research this and decide if it should influence my decision making. So, for these uncommon mutations, we don’t really quite know yet the optimal role of an EGFR TKI.

Dr Langer: By and large, most of the phase III trials that were mutation-specific really targeted the exon 19 deletion and exon 21 mutations. The one recent exception was LUX-Lung 3, which compared afatinib to chemotherapy (see NSCLC trials sidebar). It actually included some of these less common mutations, which, as you point out, are associated with therapeutic resistance, typically those in exon 20 (see EGFR mutations sidebar). I thought that was a fairly gutsy move, actually, in the design of that trial. It could have potentially sabotaged the results, and yet the trial was still quite positive, although it was a bit more positive when you just looked at the exon 19 and 21 populations (see NSCLC trials sidebar).¹³

Dr Socinski: True, but going into that trial, it was felt that 90% of the patients were going to have exon 19 or 21 mutations.

Dr Tsao: There is a growing body of literature—people are keeping track of these uncommon mutations.^14,15 As we learn more, we do know that some patients with these mutations do get 6 months PFS benefit with an EGFR TKI. So, I think that oncologists have to really become very cognizant of the subtype of mutations for EGFR.

To view the videos from this peer exchange, click here

This interchange by the faculty highlights not only the profound implications of molecular testing on the management of patients with advanced NSCLC but also the evolving nature of these approaches. As we gain understanding of the molecular drivers in lung cancer, the management of these patients is sure to evolve as well. In addition to the preceding discussion on the role of molecular testing on first-line treatment decisions, this panel of lung cancer experts also explored other key topics that impact the management of patients with NSCLC. Some of these topics will be presented in future issues of Contemporary Oncology.

References

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2. Brugger W, Triller N, Blasinska-Morawiec M, et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29(31):4113-4120.
3. Petrelli F, Borgonovo K, Cabiddu M, et al. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer: a meta-analysis of 13 randomized trials. Clin Lung Cancer. 2012;13(2): 107-114.
4. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957.
5. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3): 239-246.
6. Mitsudomi T, Kosaka T, Endoh H, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small cell lung cancer with postoperative recurrence. J Clin Oncol. 2005;23:2513-2520.
7. Jackman DM, Yeap BY, Sequist LV, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12:3908-3914.
8. Hirsch FR, Franklin WA, McCoy J. Predicting clinical benefit from EGFR TKIs: not all EGFR mutations are equal (abstract). J Clin Oncol. 2006;24:382s.
9. Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;(28 Suppl 1):S24-S31.
10. Gandara DR, Grimminger P, Mack PC, et al. Association of epidermal growth factor receptor activating mutations with low ERCC1 gene expression in non-small cell lung cancer. J Thorac Oncol. 2010;5(12):1933-1938.
11. Riely GJ, Pao W, Pham D, et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12:839-844.
12. Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol. 2008;26(15):2442-2249.
13. Yang JC-H, Schuler MH, Yamamoto N, et al. LUX-Lung 3: a randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations.Presented at the American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, Il. J Clin Oncol. 2012;(suppl; abstr LBA7500).
14. Pao Lab. Vanderbilt University Medical Center. Available at: www.mc .vanderbilt.edu/root/vumc.php?site=paolab&doc=41373. Accessed September 5, 2013.
15. Cleveland Clinical Laboratories. Technical Brief: EGFR Mutation Analysis. Available at: www.clevelandcliniclabs.com/Portals/66/PDF/TechBriefs/ EGFRMutationAnalysis.pdf. Accessed September 5, 2013.