Selection of First-Line NSCLC Therapy Influenced by Delayed Testing


During a Targeted Oncology™ Case-Based Roundtable™ event, Misako Nagasaka, MD, PhD, asked participants how they would approach therapy for a patient with metastatic non–small cell lung cancer when biomarker testing is not yet completed. This is the second of 2 articles based on this event.

Misako Nagasaka, MD headshot

Misako Nagasaka, MD, PhD

Associate Clinical Professor, Division of Hematology/Oncology

University of California, Irvine School of Medicine

Irvine, CA


A 64-year-old Asian woman presented with persistent dry cough and mild progressive dyspnea over last month, with unintentional weight loss of 8 lbs over the last 4 months​. She had a past medical history of hypertension and hypercholesterolemia​ and is a never-smoker​. Right lower lobe (RLL) auscultation revealed decreased breath sounds​. Her ECOG performance status was 1. A CT scan showed a 3.5-cm mass in RLL, small right pleural effusion with nodularity as well as mediastinal lymph nodes. ​PET/CT showed multiple bone metastases, including vertebrae and left scapula​. Brain MRI was negative for brain metastasis​. Mediastinal node endobronchial ultrasound led to diagnosis of non–small cell lung cancer (NSCLC); TTF1+ adenocarcinoma; stage IVB.

The patient is anxious to initiate therapy. What are you most likely to offer her as first-line therapy, assuming that a clinical trial is not available?

Platinum-containing chemotherapy doublet
Chemotherapy + IO triplet
IO monotherapy or IO-IO combination therapy
Chemotherapy + bevacizumab

MISAKO NAGASAKA, MD, PHD: So 60% of us [chose a] platinum-containing chemotherapy doublet; 20% of us said chemotherapy plus IO [immunotherapy] triplet, and 20% said other. In this case, I personally would choose platinum-containing chemotherapy doublet and I would like to hear the reasons from people who chose chemotherapy plus IO or other.

ROOZBEH MOHAJER, MD: I would say that…usually we get lucky and Guardant360 is back because of the proximity of their lab between 6 and 7 days. There are no circumstances for NSCLC where I don’t wait to see the EGFR status. But if I wanted to wait, then I would pick the doublet without an IO as well. But for PD-L1 [positive disease], I get impatient.

NAGASAKA: You would wait for the EGFR and ALK testing results before adding the IO?

MOHAJER: I would wait before starting therapy even if the patient is anxious.

NAGASAKA: This question does say that the patient is anxious, but we never said that she’s in visceral crisis or in a medical need to start therapy. Perhaps one of us who answered ‘other’ meant to just wait. That’s an option too. I also think that chemotherapy plus bevacizumab [Avastin] is not wrong. I don’t think there is harm in giving chemotherapy plus bevacizumab in a patient with unknown marker status in a setting of no brain metastasis, [with] no risk of brain bleed.

But we do want to avoid immunotherapy upfront when you don’t know the EGFR or ALK mutation status, because if patients are given IO up front, and then you find out that this patient has EGFR exon 19 deletion or EML4-ALK, you want to switch them to that therapy. But when you do switch, sometimes that can cause an increase in immune-related adverse events [AEs].1 Immune-related pneumonitis is well known for EGFR-mutated patients when they’ve been given PD-1 inhibitor up front, followed by an EGFR-TKI [tyrosine kinase inhibitor]. And for EML4-ALK, a similar thing happens, but it shows up more in the form of immune-related hepatitis for whatever reason.2

In order to avoid these extra AEs, you want to try to wait until EGFR and ALK results are back before you put them on IO. One might say, I don’t have to switch right away and that’s correct. You don’t have to switch right away even if the patient has EGFR and ALK [mutations]. If they were put on chemotherapy plus or minus IO or IO [alone] up front and it is working, then there might not be a need to switch right away. But eventually these patients are most likely going to progress, and eventually they’re going to need these TKIs. So you want to avoid exposure to PD-1 inhibitors upfront if at all possible, so that’s why I wouldn’t choose IO-containing regimens in this particular case when we don’t know that EGFR or ALK [status] yet.

WEI BAI, MD: So are you suggesting in general, before we have the next-generation sequencing panel back, we should not start immunotherapy at all?

NAGASAKA: That is correct, and that is for the reason I just mentioned, especially for EGFR and ALK, if you do find mutations after you’ve already given them IO and then you put them on a TKI, it increases the risk of AEs. For example, what has been reported for EGFR and pneumonitis is that the baseline pneumonitis rate with TKI is [approximately 3% to 4%].3 But that can increase up to 11% to 12% if a patient has been exposed to an immunotherapy agent prior to TKI, and it is also the reason why concurrent use is not recommended.1,4 Nobody should be getting immunotherapy and EGFR-TKI or ALK-TKI at the same time.

MIEL: What if the patient was highly PD-L1 positive? My answer would be I would still wait and get the rest of the molecular profiling results because if the patient had an EGFR mutation or ALK or ROS1, I would not give an immunotherapy upfront.

NAGASAKA: That is correct. Especially with single-agent IO, their response rates are lower than the TKIs, so you do want to wait even if the PD-L1 is high.


The patient was started on chemotherapy doublet (cisplatin and pemetrexed)​. Tissue next-generation sequencing showed EGFR exon 20 insertion mutation (V769_D770insASV)​. Four months after initiation of chemotherapy (with initial partial response), she reported worsening back pain and shortness of breath​. A CT scan showed disease progression​, and repeat brain MRI showed no metastases. She received amivantamab-vmjw (Rybrevant) as second-line therapy.

What are you most likely to offer this patient as second-line therapy, assuming that a clinical trial is not available?

Chemotherapy + bevacizumab
Chemotherapy + IO
IO monotherapy
Other TKI


1. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30(5):839-844. doi:10.1093/annonc/mdz077

2. Lin JJ, Chin E, Yeap BY, et al. Increased hepatotoxicity associated with sequential immune checkpoint inhibitor and crizotinib therapy in patients with non-small cell lung cancer. J Thorac Oncol. 2019;14(1):135-140. doi:10.1016/j.jtho.2018.09.001

3. Tagrisso. Prescribing information. AstraZeneca; 2022. Accessed February 15, 2024.

4. Oshima Y, Tanimoto T, Yuji K, Tojo A. EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer. JAMA Oncol. 2018;4(8):1112-1115. doi:10.1001/jamaoncol.2017.4526

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