Precision or Urgency? Managing PD-L1 Testing in Metastatic NSCLC

In the rapidly evolving landscape of oncology, the rush to treat is often balanced against the need to know. For patients newly diagnosed with metastatic non–small cell lung cancer (NSCLC), the interval between diagnosis and the start of therapy is a period of high anxiety, but it is also the most critical window for precision medicine.

During a virtual Case-Based Roundtable event, Martin Dietrich, MD PhD, medical oncologist with The US Oncology Network Cancer Care Centers of Brevard and an Assistant Professor of Internal Medicine at the University of Central Florida College of Medicine in Orlando, FL, discusses how clinical crossroads raise a fundamental question for modern oncologists: Is the diagnostic delay of waiting for biomarkers outweighed by the benefit of a more tailored therapeutic approach?

CASE SUMMARY

• A 66-year-old male presents with stage IV NSCLC with bone metastases
• 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-avid RUL mass, hypermetabolic mediastinal nodes, and intense FDG uptake in right scapula and T4–T6 vertebrae
  • Brain MRI: Negative
• Pertinent lab work
  • CBC: Mild anemia (Hgb 11.8 g/dL)
  • Calcium: 11.2 mg/dL
  • Alkaline phosphatase: Elevated
  • LDH: Elevated:
  • CEA: Elevated
  • EBUS-TNA: 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?

Ryan Griffin, MD: I wouldn't specifically. It seems like knowing about PD-L1 negative vs positive is important here.

Kevin Gallagher, MD: I was going to say the same thing. I agree; I always wait. [The results] don't take very long to get back. Most of the time it's not that critical to start [treatment]. The patient can wait for that information because it'll impact your treatment choice.

Martin Dietrich: For me, typically I have the PD-L1 level and I'm waiting for [next-generation sequencing (NGS)] and not the other way around. I think PD-L1 level has informative interest.

CASE UPDATE

PD-L1 testing results show PD-L1 <1%

DISCUSSION QUESTION

Given the characteristics of the patient, which regimen would you recommend?

Dietrich: Dr Griffin, what are your considerations here?

Griffin: I only have used nivolumab maybe once this year. I avoid platinum doublet. I have minimal experience in this setting. I still get—maybe because I don't have enough experience— a little uncomfortable with just the 2 cycles of the platinum doublet, especially if someone has a heavy burden of disease or visceral symptoms. That might sway me in wanting to give a few more cycles of platinum doublet, and that would be with [Keytruda] pembrolizumab.

Dietrich: And what about brain metastases? Do you use brain metastases as a as a selection factor?

Griffin: If this patient had brain metastases, I think I would be more inclined to use the CTLA-4/PD-1 inhibitor combination.

Dietrich: Dr Haddad, what about your selections between PD-1, PD-L1, and the combinations with CTLA-4? What are the factors that you take into account? How does toxicity weigh in for your treatment selection?

Philip Haddad, MD: Quadruplets are more toxic than triplets and then doublets. So, you have to look at the performance status of the patient. But technically speaking, if I have no concerns about the patient's tolerability to the regimen, I would go with immunotherapy or immuno-chemotherapy.

DISCUSSION QUESTION

Which end point do you consider to be the most impacting to your selection of a first-line immunotherapy-based regimen for a patient like this?

Ahmad Mazin Safar, MD: I think survival, of course, is the gold standard in clinical trials. But in clinic, I would argue the overall response rate is a good indication, because if you see some regression from immune therapy, that means there was an impact. At least that means there was some presentation of the antigen, and there was some responsiveness, meaning some apoptotic response. If you look at swimmer plots, the response rates usually are reported by the first scan. So, it doesn't take long to know, and then you can tell whether there is the responsiveness or not.

The other thing that, in my opinion, is very tricky, is that there are patients who are progressing on immune therapy but then go out and do extremely well with regards to survival. This is a new phenomenon, only in immunotherapy. I reported on it, and it is not uncommon. It's about 50% half of the patients who are progressing are experiencing at least a year of survival, which is a respectable amount of survival. So, there's a new interaction, in my opinion, where you may get rid of a bad clone, so size may not really change much. In fact, you may even progress, but you have impacted the disease. I think if you just go by progression alone in immunotherapy, you are taking that risk that there is going to be misclassifying of the benefit and saying immunotherapy failed when the patient will have achieved something very meaningful.

Chris Theodossiou, MD: I have a question. Is there any role for bevacizumab [Avastin] anymore?

Dietrich: It’s a very good question. We don't use the VEGF combinations much anymore. I think they didn't add that much to immunotherapy activation, but I do think they'll find a significant revival in the next generation of bispecific PD-1xVEGF antibodies. I do think VEGF as a mechanism is going to come back. I don't think it's going to be bevacizumab, but I think the mechanism is going to be very active. And I think most of the first-line immunotherapy trials now have a PD-1xVEGF bispecific backbone.