Many Oncologists Favor Consolidation Immunotherapy Following Chemoradiation for Stage III NSCLC

John Heymach, MD, PhD

During a Targeted Oncology Case Based Peer Perspectives event, John Heymach, MD, PhD, professor and Chair, David Bruton Jr Chair in Cancer Research. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, discussed the guidelines and therapeutic option for stage III non–small cell lung cancer, based on a case of a 66-year-old patient.

Targeted Oncology™: What do the National Comprehensive Cancer Network (NCCN) Guidelines recommend regarding molecular testing in this patient?

HEYMACH: I think we’ve basically hit a tipping point this year. For a while [the NCCN had recommended testing for] EGFR, ALK, ROS1, and BRAF [mutations in patients with non–small cell lung cancer (NSCLC)]. When that was the case, we were doing PCR [polymerase chain reaction testing] for EGFR and FISH [fluorescence in situ hybridization] for BRAF, ALK, and ROS1.¹ However, now we [also test for] MET exon 14 with the approval of capmatinib [Tabrecta] and for RET with the approval of selpercatinib, or LOXO-292 [Retevmo]. You could also argue that KRAS is something a lot of people would test here. We also have a drug for NTRK1, which is not a lung-specific approval, but it happens in lung cancer. That’s 7 or 8 [tests] that you have to run. From my perspective, at this point NGS [next-generation sequencing] makes the most sense. I don’t think you can do individual tests, and running individual tests is also not going to be optimal for patients.

The recommendation is a broad NGS panel now that we’ve got 7 or 8 oncogenes to look for. More are coming. I think we’re going to have HER2 drugs in the next year. Positive results were announced recently for poziotinib and for DS-8201a in the past, [which target EGFR exon 20 insertions]. I expect there are going to be drugs for EGFR exon 20 [mutations] and atypical drugs. This list is only going to keep growing, [and] it’s going to be 10 or 11 in the next few years, I expect. At this point, running individual tests doesn’t seem feasible, and shifting to NGS makes sense. [The NCCN Guidelines say] if there’s insufficient tissue to allow testing of all these, repeat biopsy and/or plasma testing should be done.

What are the therapeutic options for this patient with an EGFR mutation?

The NCCN recommendations updated in June [list] osimertinib [Tagrisso] as the preferred [therapy]. Other recommendations include erlotinib [Tarceva], afatinib [Gilotrif], dacomitinib [Vizimpro], gefitinib [Iressa], and erlotinib plus ramucirumab [Cyramza]. Erlotinib plus ramucirumab got FDA approval in May.²

Let’s say you sent a tumor sample [for profiling], but the sample was insufficient; you got another biopsy and it was [also] insufficient. I think most people would start something like chemotherapy. Then if the profile comes back while you’re [administering] chemotherapy [to a patient with] an EGFR-mutant tumor, what do you do in that case? I always try to get in either bevacizumab [Avastin], or later ramucirumab, if I think the tumor is EGFR mutant because VEGF [vascular endothelial growth factor] inhibitors work well for these patients.

What data support the use of osimertinib as first-line therapy for a patient like the one discussed in this case?

The FLAURA trial [NCT02296125] compared osimertinib versus erlotinib or gefitinib in treatment-naive patients, so [this was a] first-line treatment setting. [Inclusion criteria] indicated stable CNS [central nervous system] metastases. [Patients] didn’t have to be treated, but the patient had to be stable.³ So this patient probably wouldn’t have qualified for FLAURA, given [that] the patient was treated with radiation.

The primary end point of the study was PFS [progression-free survival]. [For] PFS, this was a strongly positive study result. For standard-of-care therapy [gefitinib or erlotinib], median PFS was 10.2 months. For osimertinib it was 18.9 months [HR, 0.46; 95% CI, 0.37-0.57; P < .001].² They’re really pushing it out pretty far, so [this is] really a significant difference.

Overall survival [OS] was also a positive result. This result was presented after the fact [at the 2019 European Society for Medical Oncology Congress]. In the final results, median OS in the osimertinib group was 38.6 months [versus the standard-of-care group at 31.8 months; HR, 0.80; 95% CI, 0.64-1.00; P = .046].³ We’ve gone from where each of our patients had a median survival of 12 months before we discovered the [EGFR] mutation, to 18 to 20 months, and now it’s 38.6 months. This is before some of the newer regimens [came] along as well. [It’s] really a significant advance for the field. It’s really a game changer.

If you look at survival by subgroup, you see a really broad benefit [for] almost everybody. For reasons I never understood, in the Asian population there wasn’t as much of a difference noted, and then something biologically I think is interesting is [that patients with an] exon 19 deletion appeared to get a lot more benefit [from osimertinib] than [patients with an] L858R mutation, the other classical mutation. Osimertinib just happens to work a bit less well. [In other studies of erlotinib, patients with L858R mutations] do worse overall; it’s just a harder mutation to inhibit effectively. [In this study] a greater benefit was noted in patients with the exon 19 deletion.^3,4

Do you face barriers to prescribing oral medications to patients with metastatic EGFR-mutated NSCLC?

I don’t know if anybody else has had the experience where the patients have to put in their income [for patient assistance programs], and sometimes they have an income of [about] $80,000 or $90,000 and don’t qualify for [assistance]. People had problems with patient assistance and the co-pay.

The last thing anybody wants is for something disastrous to happen to these patients when we have such an effective drug. You hate when you’re just sitting around in the beginning; that’s sometimes when bad things happen. I had [this experience] recently with a friend of the family. We just couldn’t get the ball rolling in the beginning and things went south, and it was a shame because if we had gotten the treatments going—it wasn’t an EGFR mutation, it was a different one—it could have made a big difference.

How do you treat patients with PD-L1–positive, EGFR-mutated NSCLC?

Remember, this patient had 55% PD-L1 expression on tumor cells. [According to the NCCN Guidelines for treatment of PD-L1–positive, EGFR-mutant cancers], contraindications for treatment with PD-L1 inhibitors include autoimmune disorders, treatment with any immunosuppressive agents, or [presence of an] oncogene. The data, even for patients with EGFR-mutant, PD-L1–positive tumors, say that PD-1 inhibitors are much less effective, even if the tumor expresses PD-L1.¹ For EGFR or ALK mutations, there have been a number of publications. We’ve found the same thing here as well.

The SITC [Society for Immunotherapy of Cancer] guidelines [address] the subsequent [therapeutic] steps: targeted therapy, chemotherapy, and then a checkpoint inhibitor.⁵ One of the things I’ve found is that after somebody has done so well on a targeted therapy for so long, once your EGFR inhibitors or ALK inhibitors stop being effective, sometimes it’s tough to get them to get the chemotherapy or immunotherapy.

When the cancer progresses, do you repeat a biopsy to see if any other mutations have developed?

This is driven in part by clinical studies. Let’s say you started with the first-generation [therapy], you’ve got a T790M mutation, you went to osimertinib, [and the cancer progresses]. Sometimes they get MET amplifications, and we’ve got a number of studies for that. You could use crizotinib [Xalkori]. When I’ve used crizotinib for MET-amplified EGFR-mutant tumors, the responses have been pretty short, but there is activity seen in that setting [and] there are very good clinical studies. There are also cases of things like RET fusions that develop as part of resistance. We’ve seen [that] the yield gets pretty low once you’ve gone through 2 lines of EGFR TKIs [tyrosine kinase inhibitors]. There’s not a lot that you find that’s useful. I think if you start with the first- or second-generation [therapy], you really have to biopsy or send a liquid biopsy. If you’ve gone through 2 generations of TKIs, then I think it becomes a little bit more of a dealer’s choice because there’s nothing that’s FDA approved after that. If you started with osimertinib and [the tumor] progresses to a C797S mutation, you can go back to a first- or second-generation drug at that point.

[For] EGFR-mutant tumors that progress on TKIs, I’ve been using the IMpower150 regimen [NCT02366143]. Its approval status in this situation is a little ambiguous, but that is carboplatin/paclitaxel with atezolizumab [Tecentriq] and bevacizumab. The study shows...some benefit from adding atezolizumab and...some benefit from adding a VEGF inhibitor. With the 4-drug regimen, you seem to get the benefits of both. It’s a tougher regimen, but that’s one I’ve been using a lot in the post-TKI setting.⁶

A study from UCLA [investigated] pembrolizumab before a TKI in EGFR-mutant, PD-L1–positive, advanced NSCLC. They put 11 patients on pembrolizumab first before a TKI. One out of 11 patients had an objective response, but it turned out that patient didn’t really have an EGFR mutation, they found out later. They had 2 deaths within 6 months of enrollment, including 1 [death caused by] pneumonitis. This really started to raise the issue of [whether] you should give immunotherapy before a TKI for these patients. Right now even in PD-L1– positive cancer, [the evidence] doesn’t support [giving] a PD-L1 inhibitor before a TKI.⁷

[In] an analysis of patients who got a PD-L1 inhibitor and then osimertinib, 15% got pneumonitis a median of 20 days after osimertinib. This really was a regimen that was hard to tolerate. Patients who received a TKI and then a PD-L1 inhibitor didn’t seem to [develop pneumonitis] at the same rate.⁸ This really makes the argument that if you think a patient might have an EGFR mutation, do not start a PD-L1 inhibitor until you’re sure they don’t [have the mutation].

[In the analysis of] immune-related adverse events in [6 patients] who got a PD-1 inhibitor and then osimertinib, almost all got pneumonitis; 1 patient developed colitis and 1 developed hepatitis. When osimertinib was combined with PD-1 inhibition [and these drugs] were used concurrently, a fair amount of hepatitis was also seen.⁸ So osimertinib plus immunotherapy, or osimertinib right after immunotherapy, seems to be problematic at this point.

A meta-analysis compared PD-1/PD-L1 inhibitors with chemotherapy [docetaxel] in patients with EGFR-mutant NSCLC. [According to the results] from 5 studies [of patients who received] immunotherapy or docetaxel, patients with EGFR wild-type tumors had a substantial benefit [from checkpoint inhibitors], with an HR of 0.67 [95% CI, 0.60-0.75; P < .001]. Patients with EGFR-mutated tumors had no benefit [from checkpoint inhibitors (HR, 1.11; 95% CI, 0.80-1.53; P = .54)]. In fact, [these patients had] a trend toward doing better with chemotherapy than with immunotherapy.⁷

The meta-analysis [shows] a pretty striking consistency among the OAK [NCT02008227], CheckMate 057 [NCT01673867], KEYNOTE-010 [NCT01905657], and POPLAR [NCT01903993] studies. In all of them, [patients with EGFR-mutated cancer had] either no benefit or slight harm with the PD-1 inhibitor as compared with docetaxel, [in contrast to patients with EGFR wild-type cancer, who had] consistent benefit [with the PD-1 inhibitor]. The studies all mirror each other closely.⁹ For patients with EGFR-mutant cancer thus far, there’s no benefit [to using PD-1/PD-L1 inhibitors], at least compared with docetaxel.

I think this raises a question. We said [to use a] targeted agent, then chemotherapy, usually a platinum doublet. If [tumors] progress after that, do you do docetaxel next or do you go to immunotherapy next? That’s something we don’t have a clear answer to yet.

When treatment with 2 lines of TKIs fail, would your next step be the IMpower150 regimen?

For a patient with good performance status, that’s what I recommend. That study compared the 3 drugs with bevacizumab versus the fourth drug, adding atezolizumab.⁶ In that study, atezolizumab did add benefit. And the question is whether immunotherapy helps [patients receiving] a VEGF inhibitor. The numbers [in the study] were modest; maybe it was just a fluke. But that was one study; we’re adding immunotherapy in that setting, and chemotherapy did seem to help. One thing I do for patients with EGFR-mutant tumors who I’m giving chemotherapy to is that I always try to get a VEGF inhibitor in. Patients with EGFR-mutant tumors really seem to benefit from VEGF inhibitors, and we’ve seen that in a bunch of different studies as well. Right now [we’re doing] a study of osimertinib with ramucirumab, testing that exact question. Another study is going on with osimertinib and bevacizumab. For VEGF inhibitors, their best place so far has actually been in EGFR-mutant disease.

What further work-up would you perform on this patient at this point?

This patient got SRS. He got osimertinib, [which is] consistent with what people are doing here. He had a great response and then eventually [developed] worsening fatigue, nausea, and loss of appetite after 18 months. Three new liver lesions [were found, and the patient’s performance status was] ECOG 1.

We notice that when tumor bulk is small, the rate of missing a mutation with liquid biopsy becomes higher. We’ve seen this in a number of different analyses, so that’s just one thing to caution people about.

[A study was conducted to characterize] resistance mechanisms to first-line osimertinib therapy [in patients with EGFR-mutant lung cancer]—in some cases, off-target resistance mechanisms, like RET fusions, BRAF [fusion], MET amplification, and KRAS [mutations]. Most of these are not easily targetable. [Some patients had] on-target alterations, like a G724S mutation or EGFR amplification.¹⁰ In some cases, a C797S mutation is observed, and that can respond to first- and second-generation therapy. Although [this therapy] is not FDA approved yet, data support that.

_Reference:

_{1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 7.2020. Accessed October 8, 2020. https://bit.ly/3iOYQ74}

_{2. FDA approves ramucirumab plus erlotinib for first-line metastatic NSCLC. FDA. May 29, 2020. Accessed October 11, 2020. https://bit.ly/3iNt3mY}

_{3. Soria J-C, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137}

_{4. Ramalingam SS, Vansteenkiste J, Planchard D, et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662}

_{5. Brahmer JR, Govindan R, Anders RA, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J Immunother Cancer. 2018;6(1):75. doi:10.1186/s40425-018-0382-2}

_{6. Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948}

_{7. Lisberg A, Cummings A, Goldman JW, et al. A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor na.ve patients with advanced NSCLC. J Thorac Oncol. 2018;13(8):1138-1145. doi:10.1016/j.jtho.2018.03.035}

_{8. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30(5):839-844. doi:10.1093/annonc/mdz077}

_{9. Lee CK, Man J, Lord S, et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced nonsmall cell lung carcinoma: a systematic review and meta-analysis. JAMA Oncol. 2018;4(2):210-216. doi:10.1001/jamaoncol.2017.4427}

_{10. Schoenfeld AJ, Chan JM, Kubota D, et al. Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer. Clin Cancer Res. 2020;26(11):2654-2663. doi:10.1158/1078-0432.CCR-19-3563}