Patient Factors Determine Treatment Selection for PD-L1 Negative NSCLC
During a live event, Neal E. Ready, MD, and participants discussed use of PD-L1 status in non–small cell lung cancer and compared the use of single agent vs doublet immunotherapy in the PD-L1–low setting.
Neal E. Ready, MD
Patients with metastatic non–small cell lung cancer (NSCLC) without actionable mutations will typically receive immunotherapy with or without chemotherapy. The PD-L1 status can guide which treatment patients can receive, as was discussed in a recent virtual Case-Based Roundtable meeting moderated by Neal E. Ready, MD, professor of medicine and member of the Duke Cancer Institute in Durham, North Carolina. In the event, oncologists discussed how they act on PD-L1 test results and how they would treat a patient with PD-L1–negative status considering how to minimize the toxicity of both chemotherapy and immunotherapy components of combination regimens.
CASE SUMMARY
A 66-year-old man presented to his physician with:
- Medical history: well-controlled hypertension on a low-dose angiotensin-converting enzyme inhibitor
- Lifestyle: active, plays pickleball 2-3 times per week, no significant functional limitations
- Family history: no known cancer history
- Social history: former smoker (20 pack-year history, quit 10 years ago), occasional alcohol use
Presenting symptoms
- Progressive fatigue over the past 2 months, interfering with his usual activities
- Persistent cough, occasionally productive with streaks of blood
- Unintentional weight loss of 10 lb in 3 months
- Intermittent right shoulder pain, worse at night, not relieved by nonsteroidal anti-inflammatory drugs
- Mild dyspnea on exertion, especially when playing pickleball
- New-onset headaches, worse in the morning
Physical examination findings
- General: Appeared mildly fatigued but in no acute distress
- Pulmonary: Decreased breath sounds over the right upper lung field; no wheezing or rales
- Musculoskeletal: mild tenderness over the right scapular region, no focal deficits
- Neurological: No focal deficits, strength and reflexes intact
Radiologic findings
- Chest x-ray: right upper lobe (RUL) mass (~3.5 cm), possible right hilar involvement
- CT chest/abdomen/pelvis with contrast: 4.2 cm spiculated mass in RUL; right hilar and mediastinal lymphadenopathy (~1.5 cm nodes); multiple sclerotic bone lesions in the right scapula and thoracic spine
- PET-CT scan: FDG (fluorodeoxyglucose)-avid RUL mass, hypermetabolic mediastinal nodes, and intense FDG uptake in right scapula and T4-T6 vertebrae
- Brain MRI: negative
Pertinent lab work
- Complete blood count: mild anemia (hemoglobin 11.8 g/dL)
- Calcium: 11.2 mg/dL
- Alkaline phosphatase: elevated
- Lactate dehydrogenase: elevated
- Carcinoembryonic antigen: elevated
- Endobronchial ultrasound-guided transbronchial needle aspiration: confirms bilateral nodal involvement with adenocarcinoma
Molecular testing
- EGFR, ALK: negative to both
- PD-L1 testing: pending
DISCUSSION QUESTION
- Do you initiate therapy for patients with newly diagnosed, metastatic NSCLC prior to knowing their PD-L1 status?
Neal Ready, MD: Do you initiate therapy for patients like this with newly diagnosed metastatic lung cancer before knowing their PD-L1 status?
Rajesh Bajaj, MD: Usually we get EGFR and ALK after the PD-L1, so we have to wait for EGFR and ALK anyway before initiating any therapy. It's never the case that PD-L1 [comes after]. We get these results in house, so PD-L1 comes very quick.
Michael Humeniuk, MD: I would say it's pretty rare not to have it, but there are a few cases where [there is] scant cellularity, or there was a glitch so they forgot to run it. I'm a heavy user of [nivolumab (Opvido), ipilimumab (Yervoy), and chemotherapy], so in most cases, I give chemotherapy and immunotherapy [IO] together. I don't really care what the PD-L1 is because the CheckMate 9LA regimen [NCT03215706] works for all PD-L1.1 I'd like to have it, and it's standard of care, but if I need to give something, I give something. The only time I use [PD-L1 status] in my first line is if I'm not going to give chemotherapy, and I need to know whether I'm going to give pembrolizumab [Keytruda] vs ipilimumab/nivolumab as an IO-only option.
Giri Raval, MD: If the PD-L1 is pending, unless I'm concerned about some visceral crisis, I'm in no rush to treat. I’d rather wait for the full set of data.
Sashi Naidu, MD: I agree. It doesn't sound like the patient is in a visceral crisis at this point,
Jigarkumar Parikh, MD: More often, if I have to treat the patient, it's going to be in an inpatient setting, if they have a recurrent effusion, and we can't get patient out of the hospital, and they get one dose of chemotherapy before they get discharged, and by then we get the next-generation sequencing results.
Ready: I think the consensus is that, since a PD-L1 is an immunohistochemistry test that most places can get in-house, and usually you can get it within a few days, it generally does make sense to wait for it, because it can help direct treatment.
CASE UPDATE
PD-L1 testing results showed PD-L1 expression was less than 1%.
Ready: When we got a PD-L1 score less than 1%, what are you all generally thinking?
Raval: There are more data for using the double IO at this point. Of course, you have to balance that against the patient's ECOG performance status and tolerability, but in this particular situation, specifically, there's benefit of using double IO.
Bajaj: It also rules out giving single-agent pembrolizumab if the PD-L1 is [negative].
Given the patient characteristics presented in this case, what treatment method would you recommend?
DISCUSSION QUESTION
- Please discuss the rationale for your preferred options(s) in the poll.
Ready: Given the patient's characteristics presented in this case, what treatment method would you recommend?
Humeniuk: He's symptomatic and he's got a decent burden of disease. The first question is, is chemotherapy needed? Because immunotherapy, singlet or doublet, don't work overnight. Are they fit for chemotherapy? He seems like it. Is chemotherapy warranted? This is high-volume disease vs 1 or 2 oligometastases that are asymptomatic. In that case, I'm saying yes to chemotherapy. So do I get chemotherapy plus pembrolizumab vs chemotherapy plus ipilimumab/nivolumab?
Frankly, especially if people are symptomatic, if you go single-agent immunotherapy, you're granting them 4 cycles of chemotherapy. This patient has adenocarcinoma, so he’ll [receive] carboplatin/pemetrexed, and he's probably going to get through that. But if it's carboplatin/paclitaxel, that's rough. Doublet IO is not that much worse. It's a tiny dose of ipilimumab added into it, so you're increasing their checkpoint inhibitor toxicity some, but not a terrible amount.
So, I find that they're better tolerated than the chemotherapy plus pembrolizumab, because you give much less chemotherapy. I can get them through 2 cycles of chemotherapy, because by the time they get 3 and 4, they're getting neutropenic fevers, they're getting neuropathies, or getting all the other chemotherapy toxicities on top of the immunotherapy vs [2 cycles]. That’s why I think about [the CheckMate 9LA regimen] even with high PD-L1, [because] I'm giving much less chemotherapy.
Ready: For someone who chose chemotherapy and single-agent IO, do you want to speak to that choice?
Bajaj: I chose that because that's what we started with, and I have stuck to that. I've heard about the dual combination in multiple settings, but I haven't seen head-to-head data saying that you must use one or the other. But my experience with chemotherapy has not been that negative. Most people are able to tolerate 4 cycles of carboplatin-based treatment. If you're going to tolerate 1 or 2 [cycles], I think you're going to be able to tolerate 3 or 4. At the most, you may have some dose adjustments for the third or fourth cycle, and we use growth factor support quite heavily, so it's not been that much of a problem. I give dual [IO] therapy in other conditions like melanoma and kidney cancer, and I think the toxicities of dual [IO] therapy are significantly higher there than PD-L1 single agent.
Ready: I think these are all reasonable thoughts. When I'm in a situation where I'm considering between the 2 in this setting, I will often...try to think what factors make it likely that the tumor has neoantigens, has proteins produced from mutant genes, where there's a significant chance, that if you enhance antigen presentation by blocking the CTLA-4, an antigen-presenting cell like a macrophage can effectively present its peptide to a T cell. Is this the kind of case where there's a good chance that those peptides are present, so it makes sense to inhibit CTLA-4? Those are the cases that that I will tend to do dual IO.
Those would be patients who are smokers, patients who have a poorly differentiated cancer, any squamous cell cancer in a smoker, or a tumor that has a high total mutational burden. All of those things make it likely that the tumor has cancer-related proteins that can be identified, and therefore I feel more compelled to give doublet IO in the PD-L1 less than 1% setting. In contrast, if I have a 40-year-old never-smoker with a well differentiated adenocarcinoma who I was sure was going to have an activating molecular alteration but didn't, and the tumor has a low tumor mutational burden, where I think that the chances of immunotherapy working are relatively low, that's where I might emphasize more prolonged pemetrexed-based chemotherapy and be less determined to give the double IO.
In cases where I think that the patient's tumor burden is not high, or they're not that symptomatic, I will use double IO without chemotherapy. There's strong evidence for that.2
DISCLOSURES: Ready previously reported honoraria from Jazz Pharmaceuticals; consulting or advisory role with Bristol Myers Squibb, Novartis, Merck, AbbVie, Celgene, Merck Serono, AstraZeneca, AstraZeneca, G1 Therapeutics, Jazz Pharmaceuticals, Regeneron, Sanofi/Regeneron, Pfizer, Regeneron, Johnson & Johnson/Janssen, Zai Lab; speakers' bureau with Bristol Myers Squibb, Jazz Pharmaceuticals; research funding from Merck. There were no other relevant dislosures.
