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Bauml Remarks on His Preference for Genetic Testing in Patients With NSCLC

Samantha Hitchcock
Published Online:4:54 PM, Fri August 10, 2018

Joshua Bauml, MD

Joshua Bauml, MD, spoke recently on the treatment options and considerations he makes when treating patients with non–small cell lung cancer (NSCLC). Bauml, assistant professor of medicine, Perelman School of Medicine, University of Pennsylvania, explained his treatment decisions based on 2 case scenarios during a Targeted Oncology live case-based peer perspectives presentation.

Case 1

A 63-year-old man presented to his primary care physician with intermittent cough and difficulty breathing on exertion. His past medical history showed hyperlipidemia, well managed on simvastatin (Zocor); hypothyroidism, managed on levothyroxine (Synthroid); chronic obstructive pulmonary disease, managed on inhalers. He recently quit smoking but had a 40-pack-year history. A physician exam showed intermittent wheezing and his ECOG performance status was 1. His creatinine clearance levels were within normal limits

A chest CT revealed a 3.1-cm spiculated mass in the right upper lobe and 2 enlarged right mediastinal lymph nodes measuring 1.5 cm and 1.7 cm; moderate emphysema noted. A PET later confirmed the lung lesion and mediastinal lymphadenopathy without evidence of distant metastases. His brain MRI was negative.

A pulmonary function test was performed and revealed a forced expiratory volume in 1 second, 1.2; diffusing capacity of the lung for carbon monoxide, 52%. A bronchoscopy with transbronchial lung biopsy and lymph node sampling revealed adenocarcinoma with positive nodes in stations 4R and 7; level 4L was negative. He was later staged with T2aN2M0, stage IIIa. Genetic testing was negative for known driver mutations.

Based on the extent of mediastinal disease and emphysema, the patient’s cancer was deemed inoperable, and he was referred for consideration of concurrent chemotherapy and radiation.

Do you typically order genetic testing for locally advanced lung cancer?

My preference is to do it on everyone, which may be a little too extreme. Even my patients with early-stage lung cancer, I will tend to check because I would like to know. Our cure rates in localized lung cancer are very poor. But I don’t know whether it is right. Certainly, in the metastatic setting, most people are doing it.

I’ve yet to have insurance yell at me when I’ve done it. But we’re also using an internal panel, and the patients are not getting stuck with the bill. That makes me feel more comfortable. If my patients were getting stuck with the bill in stage I disease, I wouldn’t do the testing. Therefore, if someone is coming into my office, I’m sending them for testing.

For adenocarcinoma, I personally do not do any polymerase chain reaction (PCR)–based testing. My exception would be for someone who, for example, is in the medical intensive care unit and a never-smoker 40-year-old woman. Then I’ll do a PCR-based EGFR test because it is fast. But from an efficiency of tissue standpoint, I don’t think there is any comparison between next-generation sequencing and a PCR-based test.

In multiple New England Journal of Medicine papers, I believe there are now more NTRK inhibitors being evaluated that actual NTRK-positive patients. I think that is an issue. But this is a target that is seen in a wide variety of tumors. I check it on all my salivary gland tumors and acinic cell tumors, but I have yet to see an NTRK. NTRK is an interesting space, and it is one of the reasons why, even for some non-adenocarcinomas, I do check.

What are the options for treatment?

I think this varies by institution, whether you want to use neoadjuvant chemotherapy or trimodality approaches, although I haven’t seen a lot of institutions using trimodality anymore. It is technically an option.

One of the things that I think is important to remember when you are thinking about concurrent chemoradiotherapy is that the incremental benefit of the concurrent chemotherapy is relatively modest. If you have a patient who is not very fit, I will give sequential therapy. I think that it is reasonable.

He underwent therapy with cisplatin/etoposide and concurrent thoracic radiation therapy and follow-up imaging showed a partial response with shrinkage of the primary and nodal lesions.

Can you comment on the design of the PACIFIC trial?

The PACIFIC study looked at patients with locally advanced, unresectable NSCLC who had completed concurrent chemoradiotherapy with a platinum-based doublet with at least 2 cycles.1 They started 1 to 40 days post chemoradiotherapy, which is interesting. That is very fast. Initially, it was even tighter, and then they expanded it because they couldn’t get people on.

The study was randomized 2:1 to durvalumab (Imfinzi), which is a PD-L1 inhibitor, versus matching placebo every 2 weeks for 12 months. There were 476 patients in the durvalumab arm and 237 patients in the placebo arm. The co–primary endpoints were progression-free survival (PFS) and overall survival (OS). 

The baseline characteristics were well balanced, and I didn’t have any concerns there, although the amount of induction chemotherapy was a little bit higher than we would generally use in our practice. They were allowed to have induction chemotherapy, but they were not allowed to have consolidation chemotherapy. That is a slight disparity from our approaches. 

What were the outcomes of this trial and their significance?

Most patients did receive therapy, but many of them did not complete the full 12 months of therapy. The PFS was much better for the use of durvalumab. What is most remarkable here is that if you think about PD-1 and PD-L1 inhibitors, the response rate is generally 15% to 20% for select patient populations. You would expect that if all we were dealing with was the effective PD-1 inhibitors given early, you would expect a 1:1 ratio in increase in therapy versus improvement in PFS. This is 12 months of therapy, and nearly 12 months of improvement in PFS. That is impressive and implies that there is some sort of synergy going on. If you take a look at the 12-month and 18-month PFS rates, it is quite impressive the difference that we are seeing here.

Taking a look at the subgroups, you can see that there was benefit regardless of histology, PD-L1 status. The PD-L1 assay used here is not the Dako 22C3 assay associated with pembrolizumab (Keytruda). Therefore, this was the assay developed with durvalumab, where the cutoff is 25%. The correlation between that assay and 22C3 is pretty good. So I feel relatively comfortable on this analysis. Interestingly, [the hazard ratio for] EGFR-mutant patients did [favor placebo], implying the incremental benefit was not as substantial. But these numbers are very small.

The overall response rate (ORR) is sort of a strange outcome, in my opinion. After chemotherapy, you have already radiated, so what are you actually measuring in terms of response? We don’t have OS data, so what they did was a modified analysis of time to distant metastasis or death, assuming that if you have distant metastasis, you are eventually going to die. You can see a clear, continued benefit for the durvalumab arm versus placebo. This was statistically significant.

What are your thoughts on the trial’s choice to begin immunotherapy so quickly after chemotherapy?

They found that if you get treatment within 2 weeks, the incremental benefit is huge. And if you have it in more than 14 days, it is much more modest. What can we take from this? Our numbers here are actually pretty substantial, with 120 people getting therapy in 2 weeks. What I do is when I have a patient who completes chemoradiotherapy, I will see them 2 weeks after treatment with a repeat CT scan of their chest. Provided they don’t have progression of their disease and they are ready to go, I will start them on durvalumab that day. I am a little uncomfortable with this because as you know, radiation pneumonitis tends to occur at 4 weeks. So, I am taking that time point and hammering it home. But if you take a look at the safety [of the PACIFIC trial], even with those numbers, the rate of pneumonitis was not substantially different between the durvalumab and placebo arms. It seems to be a safe approach, and I feel relatively comfortable with that.

Durvalumab after 2 weeks is tricky and a very aggressive move, but I talk with the patient about it at day 1. When I talk to them about the chemoradiotherapy, I say, “You’re going to get chemoradiotherapy, and then something else is going to happen. And I am not going to talk to you about it right now because it is overwhelming. But just so you know, it is coming.” The nurse practitioner I work with will also counsel them continuously and say, “Next week you’re going to see Dr Bauml, and he’s going to talk to you about immunotherapy.” For better or for worse, our patients hear about immunotherapy through direct-to-consumer advertising. Mostly for worst, but they at least know about it. It is not a completely novel approach.

The underlying principle of why this study might work, and why immunotherapy after radiation therapy might work, is that when you give radiation, you are causing apoptosis of cells and necrosis of cells, release of neoantigens, which can prime the immune system. Those neoantigens are cleared from the body very rapidly. The closer you are to that approach, the more likely you are to benefit. To me, biologically, that makes sense. There is a lot of interesting biology regarding radiation plus immunotherapy; whether it is going to be smoke and no fire, I don’t know. But there is reason to think that biologically, starting it earlier is better.

Are there any other data to support starting immunotherapy earlier?

We did a study where we looked at patients with oligometastatic disease, radiation, stereotactic ablation, and then gave them immunotherapy. We saw very long and durable responses there. It is a similar idea, this sort of amplification of neoantigenicity with immunotherapy. I don’t know the right answer, and further data are definitely needed to see what the safety is of doing it so quickly. I find this very intriguing.

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