Part 2: Discussing Brain Metastases and Immunotherapy Duration in NSCLC

Ravi Salgia, MD, PhD

Chair and Professor, Department of Medical Oncology & Therapeutics Research

City of Hope Comprehensive Cancer Center

Duarte, California

CASE SUMMARY:

A 72-year-old White man presents with chest discomfort, cough, and dyspnea. He had a history of mild chronic obstructive pulmonary disorder and was a former smoker who quit 25 years ago and had 10 pack-years of exposure.​ A CT scan of the chest and abdomen revealed a 9.0-cm spiculated mass in the left lower lobe​, loculated pleural effusion in the left hemithorax​, and right adrenal metastasis. ​

PET/CT scan showed fluorine-18 fluorodeoxyglucose uptake in the left lung mass, pleura and right adrenal gland. A brain MRI showed a solitary brain lesion of 1.5 cm but no central nervous system (CNS) symptoms​.

Physical examination was notable for decreased breath sounds in the left lung base. His ECOG performance score was 1. Lab work was unremarkable with normal organ function and blood counts​.

An image-guided biopsy of the lung mass showed a poorly differentiated adenocarcinoma of the lung​. Immunohistochemistry showed PD-L1 tumor proportion score (TPS) of 95%.​ Tissue next-generation sequencing (NGS) was negative for molecular aberrations in EGFR, ROS1, BRAF, ALK, RET, MET, ERBB2, NTRK, but was positive for KRAS G12C mutation​. The disease was microsatellite stable.

DISCUSSION QUESTION:

• What are your thoughts on the EMPOWER-Lung 1 trial data (NCT03088540)?
• ​ How many of you only use National Comprehensive Cancer Network (NCCN) guidelines and how many use pathways?

RUPESH PARIKH, MD: The question will still remain as cemiplimab [Libtayo] versus atezolizumab [Tecentriq] versus nivolumab [Opdivo] versus pembrolizumab [Keytruda]—which is better in terms of brain metastases? I don’t think they were going to compare them [head-to-head]. The cemiplimab study looked at brain metastases.¹ That doesn’t mean that the others don’t work as well unless there are some other data that I’m not aware of.

RAVI SALGIA, MD, PhD: Exactly right. We’ve seen so many dramatic CNS regressions with pembrolizumab or combined immunotherapy or other drugs. Will somebody ever compare [efficacy with CNS between these drugs]? They are produced by different drug companies, so I’m not sure that will ever happen. We can do it retrospectively, but I don’t think that necessarily helps.

If we wait another month, we’re going to have another regimen. How you gauge in terms of your clinical practice is important. Does anybody want to talk about guidelines versus pathways?

PARIKH: We’re a US Oncology practice in Las Vegas. We use the US Oncology pathways that help us. Whether you call them guidelines or pathways, we try to focus on those because we have to meet metrics on those as well.

NAUMAN MOAZZAM, MD: We are in Rocky Mountain Cancer Center, a McKesson practice. I think NCCN is much broader compared to using G2 pathways or NMI pathways. I cannot use ipilimumab (Yervoy) plus nivolumab for lung cancer without an exception.

KATHLEEN KERRIGAN, DO: I’m at an academic medical center, so I typically use NCCN guidelines, not an institutional pathway.

ARIEL SORIANO, MD: No, we don’t have any pathways where I’m at, so I just follow NCCN.

SALGIA: We’re an NCCN institution, but we also follow pathways. Some of the payers expect us to follow pathways for standardization of practice and it’s important to follow your own institutional requirements and regulatory requirements because it all depends on who the payers [is].

DISCUSSION QUESTIONS:

• For how long do you continue single-agent immune checkpoint inhibitor (ICI) for advanced NSCLC in the first-line setting? ​
• Is there a point at which you discuss discontinuation with your patients?​

SALGIA: This is an important question. How long should you continue the ICI? What are the criteria that you would use to discontinue it early on?

VISHAL RANA, MD: Generally, I prefer to continue as long as they continue to respond and as long as they’re not having any serious adverse events [AEs]. If the patient is in remission, but they start to have some life-altering AEs, I stop it then. The goal in general is to do it as long as possible, at least 2 years and beyond.

SALGIA: Does anybody not go beyond 2 years?

SAMUEL SHELANKSI, MD: I will usually treat to maximal response and then as long as the patient will allow me to continue doing so in the absence of dose-limiting AEs.

SALGIA: I tend to follow the protocol. I tend to give them up to 35 cycles for 2 years. Patients also need to have a break as well. Even after 2 years, we’re seeing a huge overall survival [OS] improvement. I’m not sure that those data exist if you continue beyond 2 years, that you’re going to have increased OS. You might cause more toxicities. At least for the protocol purposes and how we tend to follow that through, I tend to do 35 cycles for 2 years on a once every 3 weeks regimen.

MOAZZAM: You’re talking about any immunotherapy that you use, right?

SALGIA: Exactly.

HOLAVANAHALLI KESHAVAPRASAD, MD: Are there any data on treatment holidays? For example, after a year or so? Secondly, when do you decide to change the interval between treatment cycles such as 3 weeks or 6 weeks? At what point would you decide that?

SALGIA: Let’s say the 3 to 6 weeks is for pembrolizumab. I tend to do the pembrolizumab initially upfront for 2 or 3 weeks until at least 3 months. If they’re doing well and they’ve had a great response, then I’ll switch them to every 6 weeks. Our infusion rooms and our infusion chairs are very much occupied. In this COVID crisis you don’t want to expose your patients or any family members to COVID. I don’t necessarily give drug holidays unless they’ve developed toxicity. I tend to do drug holidays for cytotoxic treatments like pemetrexed or for a taxane if I need to. Those are all important things to keep in mind.

KESHAVAPRASAD: That makes sense.

DISCUSSION QUESTION:

• How likely are you to consider cemiplimab for patients with PD-L1 greater than 90% and asymptomatic brain metastases?

SHIVEN PATEL, MD: I feel l like I don’t have enough information to answer the question. If we were going to address the CNS metastases, 1 of the criteria to enroll in EMPOWER-Lung 1 was that the metastases had to be pretreated and stable. I was wondering if this patient was going to get stereotactic radiosurgery [SRS] to the brain or not since that was a requirement for all the patients in this trial.

PARIKH: That’s exactly what my point was going to be. The SRS plus immunotherapy data are very good in terms of outcomes.² I would be unlikely [to use cemiplimab in this case] unless you can tell me this drug is better and cheaper or just cheaper. Whichever immunotherapy we choose is the one that is paid for and based on our pathway. At this point in time, [cemiplimab] is not on our radar to look at.

SALGIA: [I am] very agnostic to any drug that we use, as long as we follow the American Society of Clinical Oncology [ASCO] value-based medicine. The ASCO value-based medicine teaches us we want great efficacy plus less toxicity and less financial toxicity. Those are all important in terms of our value-based medicine. I agree, and your decision is based on [your goals] as an investigator and as an attending physician at your institution working with the payers.

CASE UPDATE:

The patient was treated with pembrolizumab monotherapy, with an initial response, but when the patient returned for cycle 8, there was increasing shortness of breath. ACT scan showed progression in both the primary tumor and growth of an adrenal metastasis​.

SALGIA: Would you add chemotherapy [and/or] change the ICI therapy?

SHELANSKI: I would not continue to treat a patient with monotherapy beyond progression. In cycle 8, we’re pretty clearly beyond any sort of pseudoprogression issues on the scan. I would certainly be looking at change in therapy at this point.

SALGIA: I agree completely. In our lung cancer setting, we don’t see as much pseudoprogression as we do in the melanoma setting. It’s important to change therapy, if that makes sense. Will the KRAS G12C-targeted therapy be effective by itself? That’s to be determined still because the patient’s tumor burden is so high, but that’s an option. Sotorasib [Lumakras] has been approved and I think that could be an option.³ Or chemotherapy is a very good option as well. I think any one of those can be utilized.

_References:

_{1. Sezer A, Kilickap S, Gumus M, et al.Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomized, controlled trial. Lancet. 2021;397(10274):592-604. doi: 10.1016/S0140-6736(21)00228-2.}

_{2. Suwinski R. Combination of immunotherapy and radiotherapy in the treatment of brain metastases from non-small cell lung cancer. J Thorac Dis. 2021;13(5):3315-3322. doi:10.21037/jtd-2019-rbmlc-08}

_{3. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. Published May 28, 2021. Accessed April 13, 2022. https://bit.ly/3vdNZvu}