Broad Panel Testing Is the First Step in Tailoring Treatment Throughout Lung Cancer

Jacob Sands, MD

Broad panel testing with tissue- or blood-based next-generation sequencing (NGS) should be part of the initial workup of a patient with early-stage and metastatic non–small cell lung cancer (NSCLC) followed by PD-L1 testing, said Jacob Sands, MD, who added that the results have direct implications on adjuvant and frontline therapy decisions.

“It’s exciting that we’re talking about all new drugs that have defined the standard of care over the past 10 years. This is a new era we’re in; it’s both the era of targeted therapy and the era of immunotherapy. It’s crucial to make sure that you’re doing the appropriate testing to decipher what is the best treatment is for each patient,” Sands said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on Precision Medicine in Lung Cancer.

In the interview, Sands, a physician at Dana-Farber Cancer Institute, as well as instructor of medicine at Harvard Medical School, discussed biomarker testing in lung cancer, the utilization of neoadjuvant and frontline immunotherapy, and targeted therapy advances in NSCLC.

OncLive^®: What were some of the key discussion points from the meeting?

Sands: We covered the broad topic of genomic testing and started out [by discussing] the importance of genomic testing and biomarker assessment, which should be the first part of deciding what treatment to give to patients. In someone who is diagnosed with metastatic nonsquamous NSCLC or squamous [disease] without a significant smoking history, it’s important to do genomic testing first.

Michael Cheng, MD, of Dana-Farber Cancer Institute, kicked off the meeting with an excellent talk about biomarker testing and genomic testing. I gave a talk on immunotherapy, which is mostly [recommended] in patients without an actionable alteration, although there are some exceptions to that. We discussed the huge effect immunotherapy has had [on practice] and which regimens we’re using. We also had excellent talks by Julia Rotow, MD, of Dana-Farber Cancer Institute, and Ibiayi Dagogo-Jack, MD, of Massachusetts General Hospital, covering what has become a very broad topic of actionable alterations and targeted therapies. It’s really exciting that in the past 13 years since the IPASS trial [NCT00322452] was published, we now have so many different alterations and approved targeted therapies.

NGS testing is overwhelmingly important. If there’s an actionable alteration with an approved therapy, and now there are a number of these, then it’s important to understand each of those and the setting for use. In many cases, it’s a first-line therapy in the way that I practice, although there are some [alterations for which] I tend to [reach for targeted therapy] in the second-line setting. After doing NGS testing is [when we should evaluate] PD-L1 expression and consider immunotherapy [if the patient doesn’t have an oncogenic driver].

Dr Cheng discussed biomarker testing. Why is it imperative to use broad molecular testing up front?

Dr Cheng made the point that there are so many alterations now with approved therapies, which has further strengthened the importance of NGS and full panel testing. This can be done by blood-based testing or tissue-based testing, and that’s a discussion to be had. Tissue-based testing has been the gold standard. Blood-based testing can be done a little bit more rapidly currently, but each of them has a role. The biggest thing is to make sure that we are detecting an actionable alteration, if one is present. That is the most important aspect to biomarker testing at this point.

There is now a discussion around tumor mutational burden [TMB]. In my practice, that is not really something that I’m utilizing as far as decision making. There is some interesting research around that. There’s a bit more to clarify around TMB [with] ongoing research that I’m following.

The biggest thing is actionable alteration detection. We saw data released at the 2021 ASCO Annual Meeting—and I applaud the group that released this—showing that only about half of patients were adequately tested for actionable alterations. This is a disservice to the patients that are being missed. Targeted therapies are, in many cases, the best treatment for patients [with certain alterations]. I’m not using targeted therapy as frontline therapy for every alteration, but to not detect [the alteration] and to not know about that limits options for those patients. In some cases, [targeted therapy] truly is the standard of care.

The bulk of any biomarker discussion is around detecting genomic alterations. NGS panels are the way we would do that. I’ve had the experience of having a patient who has had had multiple lines of treatment. We were then talking about hospice, [and then it] turned out we were about to open a study for RET fusions. At the time I detected her RET fusion, there was no trial being developed, but she was one of the first patients into one of the trials that [served as the basis for the] FDA approval of the RET inhibitor and she benefited tremendously from that agent, which was only possible from having detected the alteration in her prior NGS panel. This broad testing goes beyond the currently approved therapies to what else is possible as other drugs are developed.

Pivoting to your presentation on neoadjuvant and frontline immunotherapy in NSCLC, what have been some of the most significant studies in this space? What are you using to guide treatment recommendations?

This is an exciting time because we’re seeing immunotherapy now at the center of treating patients in the stage IV setting. Genomic testing should be done first.

Prior KEYNOTE trials have led to pembrolizumab [Keytruda] becoming standard of care. KEYNOTE-024 [NCT02142738] evaluated pembrolizumab alone in patients with PD-L1 expression greater than 50%. KEYNOTE-042 [NCT02220894] included patients with less than 50% PD-L1 expression, but the data from that trial really have not altered how I practice. Broadly, people are using pembrolizumab alone for patients with greater than 50% PD-L1 expression and chemotherapy plus pembrolizumab for those with less than 50% PD-L1 expression. That is kind of the base upon which now we discuss the CheckMate 227 trial [NCT02477826], which led to FDA approval of nivolumab [Opdivo] plus ipilimumab [Yervoy] in patients with PD-L1 expression greater than or equal to 1%. In that trial, the comparison was with chemotherapy alone, and that trial did show a statistically significant improvement [in overall survival (OS)].

We also discussed CheckMate 9LA [NCT03215706], which was a study of nivolumab plus ipilimumab plus 2 cycles of chemotherapy vs 4 cycles of chemotherapy [in all-comers], and that [regimen] also led to FDA approval.

In terms of where I use these regimens, I use pembrolizumab alone or chemotherapy plus pembrolizumab as my standard. Ipilimumab, the CTLA-4 inhibitor, adds a bit more toxicity, and the real benefit of ipilimumab is somewhat unclear. To analyze what’s best for patients, you must do cross-trial comparisons, which we don’t have a statistical basis for. However, in clinical practice, what we’re doing is asking what the best treatment is for this patient.

We also discussed CheckMate 816 [NCT02998528]. This was a neoadjuvant study of nivolumab plus chemotherapy vs chemotherapy alone. We saw deeper responses within that study [with the addition of nivolumab]. This study looked at the major pathologic response as well as pathologic complete responses, and the addition of nivolumab to chemotherapy had a meaningful effect on [those end points]. It’s exciting that we’re now looking at immunotherapy in the neoadjuvant and adjuvant settings. In this case, the neoadjuvant setting.

The one concern with this study was the number of patients that didn’t go on to get surgery or had surgery delayed. [We must consider that because] there may be real benefits to patients getting systemic therapy earlier given that our concerns are more about distant recurrence as opposed to localized [recurrence] from where the mass is resected or within the mediastinum.

We also discussed the IMpower010 study [NCT02486718], which led to FDA approval of atezolizumab [Tecentriq] after adjuvant chemotherapy in patients with stage II to III disease by 7th edition staging and PD-L1 expression of greater than or equal to 1%. In this study, we saw better disease-free survival [DFS] in the group that was randomized to atezolizumab vs best supportive care. Patients with 1% to 49% PD-L1 expression didn’t have as much of a benefit as what we saw from the greater than 50% PD-L1 expression group. That group with greater than or equal to 1% PD-L1 expression, which showed statistical significance in the study, may be pulled a bit by the greater than 50% PD-L1 expression group. As these data mature, we will see the effect that makes to OS, but that is an exciting advance in the field.

I also took the opportunity to discuss the ACCIO trial [NCT04267848], which I’m leading through the cooperative group. This is within the ALCHEMIST [NCT02194738] umbrella. This is a study that was originally designed as a 3-arm study of adjuvant chemotherapy followed by observation vs chemotherapy followed by pembrolizumab vs chemotherapy plus pembrolizumab followed by pembrolizumab. In both of those arms, patients will get only 1 year of pembrolizumab. That trial is being amended to examine sequential vs concurrent treatment given the FDA approval of adjuvant atezolizumab.

We’re very excited that the IMpower010 and CheckMate 816 studies have validated this concept of including immunotherapy in perioperative treatment. We’re very excited now to be able to look at sequential vs concurrent therapy in that setting, as well.

Moving to the presentations Dr Rotow and Dr Dagogo-Jack gave on targeted therapy, what alterations are you now testing for in your practice?

The IPASS trial was the first demonstration of the power of targeted therapy. This was done with a first-generation EGFR TKI vs chemotherapy.

We’re now seeing an increasing number of alterations. Of course, there are EGFR, ALK, and ROS1, which were the first ones. MET is now added as is RET, for which we now have 2 different FDA-approved inhibitors, and the list continues with BRAF V600E, NTRK, and now EGFR exon 20, which has been a topic of discussion because there was a recent approval. KRAS G12C is now also a topic. KRAS has been known for a long time but has been difficult to target.

[How to appropriately treat these patients] goes back to the importance of what Dr Cheng outlined, with the importance of adequate genomic testing through NGS panels. Dr Rotow and Dr Dagogo-Jack rounded out an exciting array of different treatment options that are new over the past decade and how much the field has changed. It’s exciting because I don’t think the public or even many physicians in the medical field outside of oncology realize the advances that have happened in the past decade, but we’re working with entirely new drugs over the past decade in lung cancer.

Various chemotherapy backbones still play an important role. Chemotherapy still plays an important role in the second-line setting and beyond. Previously, docetaxel was the standard second-line option. There are so many new options now. Looking ahead, there is a lot in development with antibody-drug conjugates, for example, and some other novel immunotherapies. There’s so much happening in the field that 10 years from now, I expect that there will be an entirely different set of drugs that we’re discussing as first-line options.

Returning to adjuvant therapy, what are your thoughts on osimertinib’s movement into the adjuvant setting for patients with EGFR mutations?

It makes a lot of sense to take drugs that we know work well in the metastatic setting and then evaluate them in other settings, such as earlier-stage disease. The ADAURA trial [NCT02511106] took patients that completed their adjuvant chemotherapy, or for whatever reason, didn’t get adjuvant chemotherapy and then randomized them to get osimertinib or placebo. What we see from this is a dramatic improvement in the DFS for those who got osimertinib. In the metastatic setting, the response rate is very high, and the durability is [there], and with a median progression-free survival of 19 months, it’s not surprising to see this improvement in the DFS in the adjuvant setting. The big question is: Is this going to translate to an OS difference? There was quite a bit of debate about that and its use around the time of the FDA approval.

We always ask the classic question: If I were in this position, what would I want? The AE profile is usually minimal, although there can be some exceptions to that, but broadly, this is a well-tolerated drug. The agent is so effective in [improving] DFS, particularly in stage II/III disease; those curves separate a lot, so I’m more inclined to use it in those cases. When you’re talking about stage IB disease, the data are not as convincing. That might be a setting where there’s a bit more discussion about what to do. It’s a tough call. From the beginning, when you don’t have all the information, academically we all say, “Well we want more, we want to see OS, but right now, we don’t have it.” If I were in that position, I would be more inclined to take it given how impressive the DFS difference is and how well tolerated osimertinib is.