Identifying Situations Where CTLA-4 Addition Improves NSCLC Outcomes
During a live event, Neal E. Ready, MD, and participants discussed what factors justify using PD-1 plus CTLA-4 inhibitor and chemotherapy in patients with non–small cell lung cancer in the PD-L1–low setting.
Neal E. Ready, MD
In patients with metastatic non–small cell lung cancer (NSCLC) whose PD-L1 status is negative, trial data support the addition of immunotherapy (IO) to chemotherapy. However, other patient factors can shape the decision of whether patients should be given both a PD-1 and CTLA-4 inhibitor. In a 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, oncologists discussed the difference in the value of PD-L1 status in guiding treatment with IO in lung cancer vs skin cancer and which cases would warrant the addition of CTLA-4 inhibitor to give patients a better chance to benefit from IO.
This article is part 2 of a 2-part series from a Case-Based Roundtable event.
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
- Negative for EGFR and ALK alterations
- PD-L1 testing: pending
DISCUSSION QUESTIONS
- Please discuss the rationale for your preferred options(s).
- What factors impact your systemic therapy approach for advanced NSCLC with PD-L1 expression less than 1%?
Neal E. Ready, MD: What sites of metastasis, mutational status, histology, and other things would sway you one way or another in your treatment choices for somebody with an adenocarcinoma and PD-L1 less than 1%?
Jennifer Atlas, MD: As a melanoma and cutaneous [cancer specialist], this is always a struggle for me when I see these patients with lung cancer, because I know PD-L1 status matters so much more in [NSCLC]. We don't use it to decide our treatment decisions in melanoma. With this patient being more symptomatic, with a higher tumor burden, lack of a driver mutation, and low PD-1 status, that was what drove me to choose dual IO plus chemotherapy in this particular case.
Giri Raval, MD: It makes perfect sense that if your patient has a more immunogenic tumor, more TMB [tumor mutational burden] and things like that, to use double IO. If they don't have any of those, then you don't use double IO, and you go with a single IO. Is there a role for IO [alone] in that subset of patients?
Ready: There is, but the thing is, PD-L1 is not a binary biomarker. Everybody will see a few patients who are never-smokers with PD-L1 less than 1% who have an immune response. You can still see an immune response, and the responses to IO are so durable. [Because] that's the only hope for years-long response, with a few rare exceptions, I think that everybody deserves a shot for the IO. The ones that I was discussing were the never-smoker with well-differentiated adenocarcinoma, PD-L1 less than 1%, and very low TMB. When you start adding all those things together, I don't think that the risk of the dual IO adverse events justifies the likelihood of benefit.
There are data for all of this around the histology benefiting more from this, poorly differentiated cancers benefiting more from double IO. When we compared data for CheckMate 817 [NCT02869789] and CheckMate 568 [NCT02659059] with hundreds of patients treated with double IO therapy and from CheckMate 227 [NCT02477826] and CheckMate 9LA [NCT03215706]—when you looked at all of them, the ones with poorly-differentiated disease were much more likely to benefit than those with well-differentiated disease.1-4
Michael Humeniuk, MD: There's also a great second-line trial [NCT02888743] in people who had [disease refractory to] single-agent checkpoint inhibitor. Everyone received durvalumab [Imfinzi] and tremelimumab [Imjudo], and it was a 3-arm trial with radiation therapy that had to do with the abscopal effect. The answer was [the radiation therapy] didn't work….5 But the interesting about the trial is that these people all [had disease refractory to] single agent but there was a 10% response rate on all arms. These people are…just getting CTLA-4 with PD-1. So, I think across the board, like Dr Ready said, there are people who don't need doublet in some cases.
I specialize in skin cancer as well, so I have seen a ton of [cutaneous] squamous cell carcinomas that are horrible and they disappear with pembrolizumab [Keytruda], and it's beautiful. Yet I've had a few patients [with progression], and I've put them on ipilimumab [Yervoy] plus nivolumab [Opdivo] and have had responses, but do I need them out of the gate? No, I can use pembrolizumab out of the gate for most of my squamous cell carcinoma cases. But the problem is that unlike lung cancer, I can see my patient with skin cancer. I know in 3 to 6 weeks that it didn't work, and I have to do something else. With lung cancer…it’s going to be unknown for a while [whereas] it’s going to be a lot more unmasked in skin cancer.
Ready: There was the KEYNOTE-598 trial [NCT03302234] of pembrolizumab with or without ipilimumab in tumors with PD-L1 greater than 50% based on some very early data from the early ipilimumab/nivolumab trials, and that was a negative trial.6 So if the PD-L1 score is greater than 50%, especially if it's 80% to 100%, there's probably no role for PD-1 plus CTLA-4 dual inhibition. With less than 50%, it's a reasonable consideration. Focusing on those with PD-L1 expression less than 1%, I think there's a particular potential benefit of getting an immune response with doublet IO, where you may not get it with single IO.
What about different mutational status? In our adenocarcinoma case, we already went over checking EGFR and ALK. What particular mutations would dissuade us or encourage us to do different treatment options?
Gary Thomas, MD: Aren’t the mutations KEAP1 and STK11 particularly sensitive to this dual IO approach?
Ready: Yes, very good. About 30% of adenocarcinomas are KRAS mutated and driven through KRAS. It's the most common oncogenic driver in NSCLC. There's a significant percentage of tumors that are KRAS mutated that are co-mutated with either SDK11 or KEAP1 and the double-mutant genotype is incredibly immune resistant to single PD-1 checkpoint, with less of a chance of getting a response than [in tumors with] PD-L1 expression less than 1% by itself. The KRAS compound mutations with SDK11 and KEAP1 are really immune resistant. There are pretty good data from the larger trials suggesting that dual IO has the potential to overcome that resistant genotype.7 So that's a consideration. Just as an aside, there are some early trials suggesting that AXL inhibition may also be able to overcome SDK11.8
Sejal Dave, MD: Is it mainly on KRAS non-G12C mutations?
Ready: Any of them. It’s not specific to KRAS G12C. Any of the KRAS oncogenic drivers can be co-mutated with SDK11 and KEAP1.
Dave: If you see a TP53 mutation, would you be more inclined to use this IO combination regimen?
Ready: That's a tough one. I'm not aware that the data are that much stronger. But the TP53 mutated tend to be worse and more aggressive cancers. They're going to tend to be the ones that are smoking related, more aggressive cancers to begin with. I’m not aware of data to suggest we should use dual IO particularly in the TP53 cancers.
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.
