ILCN Editorial Group member Shirish M. Gadgeel, MD, is Chief of the Division of Hematology/Oncology at the Henry Ford Cancer Institute/Henry Ford Hospital. Dr. Gadgeel is currently working, in conjunction with four other institutions, on a phase II study evaluating pembrolizumab plus chemotherapy in patients with EGFR mutation positive and ALK translocated NSCLC previously treated with appropriate TKIs.
ILCN: Can you please tell me about the single-arm, phase II study using pembrolizumab plus chemotherapy for patients with EGFR/ALK mutations?
Dr. Gadgeel: This is a multi-institutional trial that is evaluating the combination of chemotherapy and pembrolizumab for patients with EGFR-mutated and ALK-translocated NSCLC. Previous studies have found this combination to be successful for treatment- naïve patients with wild-type EGFR/ALK and nonsquamous NSCLC,1 but checkpoint inhibitors alone tend to be ineffective for patients with EGFR/ALK-mutated disease. Targeted therapies have been exhausted for the patients included in this trial. In almost all of these types of patients seen in clinic, we must eventually administer chemotherapy, resulting in immediate PFS of approximately 5 months and a response rate of approximately 30%.2 And we want to see if addition of pembrolizumab improves their outcome.
One of the questions that we are trying to answer is whether the Impower 150 regimen,3 which is currently a regimen considered in clinical practice for this patient population, is actually the best regimen. Because Impower 150 studied four drugs (atezolizumab/bevacizumab/carboplatin/paclitaxel), it can obviously be more toxic. It is not clear, however, whether all of these patients require all four drugs to benefit. In addition, pemetrexed is thought to be one of the most effective agents in patients with EGFR/ALK mutations, whereas the Impower 150 regimen involved carboplatin and paclitaxel. Therefore, it is not clear whether you would see a similar benefit with carboplatin/pemetrexed and coupled with pembrolizumab. We currently have a total of approximately 25 patients enrolled, 18 of whom are EGFR positive and seven of whom are ALK positive. Our hope, although it is not clear that we will be able to reach our goal, is 27 patients in each group.
Patients will receive four cycles of carboplatin, pemetrexed, and pembrolizumab. After four cycles, the carboplatin is discontinued. Pemetrexed and pembrolizumab can be continued for a total of 2 years if the patient is tolerating the treatment well and if the disease is controlled,
ILCN: What kind of timeline is the trial on for enrollment?
Dr. Gadgeel: The study has been going on for 2 years. We have just recently added Cleveland Clinic, and we are hoping that they will help us enroll a bit faster. One of the issues about this study is that this is an approved regimen, so physicians can use this regimen even off-trial. Our hope is that, by conducting the trial, we determine how beneficial this combination is, rather than just assume as some clinicians already are doing in practice. We also are performing some correlative studies and hoping that that can better answer the question of how beneficial the addition of immunotherapy is to chemotherapy. We think we are going to need at least another year to have sufficient enrollment.
ILCN: In terms of your own practice, how many times do you prefer to radiate before you switch treatments in this population?
Dr. Gadgeel: I have started integrating radiation in two different ways. Many patients I see have oligometastatic disease. To me, oligometastatic is generally defined as less than three sites, although the definition of oligometastatic disease is different in different trials. I typically start with appropriate systemic therapy for these patients. If systemic therapy results in a very good response, then I will consider radiating the disease sites that were involved at baseline, usually 3 to 4 months after initiation of systemic therapy. There is a subgroup of these patients, however, who do well on systemic therapy, particularly targeted therapy but eventually develop oligo-progression. That is, they may or may not have had oligometastatic disease at diagnosis but, when the disease does progress, it is only in one or two areas. Usually, I would not consider adding radiation if progression was in more than a couple of sites. I have considered adding radiation or, very rarely, even surgery, if it is oligo-progression. I am much more likely to consider radiation therapy if the patient has had benefit for a year or more. If they have been on therapy for 6 months or fewer, and then they have progressed, I am much more likely to consider switching treatment. Because the likelihood that these patients are going to experience disease progression in other sites relatively quickly is high enough.
If there is limited progression in the brain and only in the brain, I may consider local therapy. However, now there are drugs that penetrate the CNS and can treat brain metastases. Therefore, for oligo-progression in the brain both local therapy and switching to a brain penetrant drug are options. Generally this decision is made after consulting with radiation oncologist and/or neuro-oncologist
ILCN: You mentioned you sometimes consider surgery. Can you talk a little bit about the conditions for that?
Dr. Gadgeel: This situation is very rare and is usually considered for those patients who have brain metastases, particularly if the brain metastasis in the posterior part of the brain. In that portion of the brain, these lesions can cause significant complications if they grow. Resection can also be considered for patients with adrenal metastases. Though surgery can be considered at other sites it is quite rare.
ILCN: How well are patients tolerating your study treatment?
Dr. Gadgeel: In my personal clinical experience, patients with EGFR/ALK mutations do not tolerate chemotherapy as well as those patients who receive chemotherapy in the first line simply because they usually have metastatic disease and have been on targeted therapy prior to starting the chemotherapy. I typically see a little more fatigue and cytopenias in these patients. Among the patients I have treated on the trial I have observed these adverse effects. We await the analysis of all enrolled patients to determine if the tolerability of this combination is similar to the adverse events observed with this therapy when administered as the first therapy in advanced NSCLC patients.
ILCN: Because of this, do you think checkpoint inhibitors should be reserved for third- or fourth-line treatment? Do you have any observations for real-world clinical practice?
Dr. Gadgeel: At the present time the role of immune checkpoint inhibitors for the treatment of EGFR/ALK altered NSCLC patients is unclear. Single-agent immune checkpoint inhibitors are not very effective in these patients. So, if immunotherapy was being combined it should be considered in combination with chemotherapy, However, the efficacy of such regimens in these patients is not well defined.
It is important to note that, in real-world clinical practice, we sometimes get the PD-L1 test result before we get the results of the gene alterations in the tumor. Because of this, there may be a tendency to start the patient on immunotherapy before getting the full gene alteration analysis report. A number of case reports have illustrated (this has not been studied prospectively) the development of significant toxicities in patients who received a checkpoint inhibitor and then was subsequently switch to a targeted therapy. Because of this, one needs to be very mindful to use immunotherapy very appropriately; that is, only after the results of the genetic analysis have been obtained and targeted therapy has been ruled out. Only then should we use the PD-L1 result to guide us as to how to use immunotherapy for those patients.
- Rodriguez-Abreu D, Powell SF, Hochmair M, et al. Final analysis of KEYNOTE-189: Pemetrexed-platinum chemotherapy (chemo) with or without pembrolizumab (pembro) in patients (pts) with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 9582-9582.
- Soria J-C, Wu Y-L, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015;16(8):990-998.
- Socinski M, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378:2288-2301.