Molecular Testing Results Are Critical Amid an Expanding Targeted Therapy Paradigm in Advanced NSCLC

Julia K. Rotow, MD

In advanced non–small cell lung cancer (NSCLC), the surge of targeted therapy options for patients who harbor actionable molecular alterations has shed light on the importance of waiting for the results of next-generation sequencing (NGS) and blood-based testing when possible, said Julia K. Rotow, MD, who added that initiation of immunotherapy in patients who are eligible for targeted therapy can be significantly detrimental to their outcomes.

“It is important to have all the data back before starting [a patient on] treatment so we know that we are starting with the most effective therapy while giving space to sequence therapies as safely as possible,” said Rotow, a medical oncologist at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute. “The way I phrase it for my patients is that we always have the option to start a more generic initial treatment plan with a standard, platinum-based chemotherapy doublet.”

In an interview with OncLive®, Rotow discussed how she approaches molecularly testing in patients with liquid- and tissue-based biopsies, the importance of waiting to initiate immunotherapy until a patient’s molecular testing results are confirmed, and other nuances that she considers when treating patients with advanced NSCLC.

OncLive®: Do you always recommend concurrent liquid- and tissue-based biopsies for patients with advanced NSCLC?

Rotow: We have two major strategies now available to us: tissue-based testing on tumor biopsy or tumor cytology and liquid-based assays. Each [testing strategy] has advantages. Certainly, tissue-based testing allows for potentially higher sensitivity and more comprehensive testing panels in the form of NGS. [Therefore], we do still consider [tissue-based testing] our gold standard when we want to be sure our patients had full genomic profiling at diagnosis or at treatment resistance.

However, liquid-based testing offers a number of advantages. [Liquid-based testing] is noninvasive [because] it is based on a blood draw, and the results typically come back more quickly [compared with tissue-based testing]. Our modern cell free DNA–based assays do cover all the current actionable genomic alterations, as well as a number of acquired resistance alterations.

Both [testing strategies] have a place in patient care. My recommendation is to always include tissue-based NGS [in the patient’s workup]. For many patients, I will add a concurrent liquid-based assay, simply because we know that time can matter for our patients. [Liquid-based testing] may allow us to get results that may be actionable back faster and earlier in patient care.

How important is it to wait for the results of molecular testing before initiating therapy?

We do know that having all the data back for both immune status via PD-L1 [testing] and molecular status via, ideally, an NGS assay, will allow for better selection of a more personalized treatment approach for patients. [This allows us] to give patients what we believe to be the most optimal first-line therapy for their individual disease.

There are exceptions to this. Certainly, for patients with adenocarcinoma or a patient in which perhaps testing is less critical but the need to start treatment is urgent, sometimes we have to bypass testing and proceed with treatment. We have to recognize that that is sometimes required.

Why is immunotherapy inappropriate for some patients with advanced NSCLC who harbor actionable driver alterations?

This gets back to the question regarding [whether we should] wait for NGS [testing results] to come back or not. Our current standard-of-care option for most patients without an actionable alteration is going to include immunotherapy, which has transformed care for many patients.

However, for patients with molecularly targeted drivers, we know that immunotherapy is not an optimal first-line option. [Patients] will have better responses to their molecularly targeted agent, so whenever possible, I like to start therapy with those agents. Secondly, we know that the inclusion of immunotherapy could offer less benefit for patients. These data are still being developed and understood, but we know that for many of our patients with a molecularly targetable alteration, such as young, nonsmokers with EGFR mutations or ALK rearrangements, the response rates with immunotherapy have been lower compared with the general population. [These patients’] potential for benefit is lower on these drugs.

Lastly, there are some emerging concerns about the risk of combination therapy with many of our targeted agents and immunotherapy with checkpoint inhibitors. For example, reports [have shown] higher rates of pneumonitis, which is certainly a serious consequence of therapy in patients who received checkpoint inhibitors and EGFR-targeted drugs [vs a single-agent approach]. Similarly, for some of the ALK-targeted agents, we’ve seen reports of higher rates of hepatitis with a combination strategy [compared with targeted therapy or immunotherapy alone].

Beyond that, we know that because immunotherapy agents are antibody based, they remain in circulation [within the body] to modify the immune system for potentially a prolonged period of time after treatment. There is some tail effect where, even in transition between an immune-based therapy and a targeted therapy, [that sequence] may hold elevated risk. [That risk is present] even if the drugs are not given simultaneously during treatment.

How do you approach initiating treatment for a patient who requires immediate therapy and cannot wait for the results of molecular testing?

My treatment approach to this situation depends on the patient’s probability of benefitting from immunotherapy, the probability of them having an actionable alteration, and the clinical urgency of the situation. I try to balance those 3 factors to make a choice for what therapy to give in the first cycle of treatment for a patient with newly diagnosed disease, [as well as to determine] how long I should wait for the molecular testing results.

For a patient who has a high probability of an actionable alteration, if at all possible, I wait [for molecular testing results]. These are young, non-smoking patients who are more likely to have a classic EGFR, ALK, or ROS1 mutation [vs older patients who smoke]. In these patients, if I am forced to start therapy because the clinical situation warrants treatment immediately, I will defer the inclusion of a checkpoint inhibitor in cycle 1 and simply give a platinum doublet to gain some disease control. This is certainly an off-label strategy, but it can offer a balance between starting treatment and safely regarding timing of checkpoint inhibitor initiation.

For patients with [a] moderate risk [of harboring an actionable alteration], I will sometimes wait for the liquid-based testing [results]. I will get that back within 7 to 10 days. If those results are negative, the probability of finding something actionable is low. If there is a strong clinical imperative to begin treatment, I may go ahead and start on triplet therapy from cycle 1.

It is always very important when I’m considering dropping immunotherapy in the first cycle to be aware that [patients in] the clinical trials [that evaluated] these regimens received triplet therapy from the beginning. [The triplet regimen] is what demonstrated clinical benefit, so a risk/benefit conversation always needs to be had with the patient for full transparency of following that strategy.

What strategies are in place to try to overcome the barrier of access to molecular testing in advanced NSCLC?

As testing in oncology becomes more complex and we have more treatment options, the challenge [of access to molecular testing and appropriate therapy] is only going to increase. The increase in mainstream availability of broad NGS testing and liquid biopsy is helping us in this setting. [Liquid biopsy] can be done just about anywhere so patients can get access to that testing.

Not all patients live in or near a major city, [nor does every patient] have the resources to travel for that care if needed. The rise of telemedicine during the COVID-19 pandemic has certainly also been helpful for our patients and colleagues in the community because it is much easier to get access to academic second opinions. Many of our patients benefit from a chance to have more than one opinion at the start of treatment because it gives them greater confidence and comfort moving forward, which is really important. [Telemedicine] also gives us a way to try to identify patients who may benefit from access to a clinical trial early in their care or at resistance to standard therapies. [We get] a chance to review what is available and see whether it is feasible to get the patient access [to those studies].

Do you recommend repeat molecular testing for patients with advanced NSCLC?

I’ve talked a lot about doing up-front testing to get all the data to [ensure] we are starting the best therapy for the individual patient up front. However, [testing] is also very important in later-line treatment as well, especially for patients receiving targeted drugs or those who have access to immunotherapy. Repeat profiling can be very important to make sure we know about every option available to these patients. Many of our targeted agents now have later-line [indications] or [are being evaluated in] later-line clinical trials that could allow patients to defer second- or later-line chemotherapy. We’d like to expand our list of trial options available for patients whenever possible.

How do you foresee the field of targeted therapy expanding in the coming years? Will some of these targeted options be moved to earlier stages of disease?

[It is important] to be aware of the new developments happening in lung cancer because the field has been moving very quickly. We currently have 7 targets that we have personalized drugs for, but we expect to see others join that list in the near future, including KRAS G12C. A number of agents are in development and moving forward in clinical trials [targeting KRAS G12C mutations]. HER2 exon 20 insertion mutations [are also emerging] as an actionable target. A number of drugs, including [fam-trastuzumab deruxtecan-nxki (Enhertu)], an antibody-drug conjugate, and TAK-788, a [HER2-directed TKI], have been moving forward in trials.

In watching the targeted [therapy landscape], we are going to see more options for our patients, including patients who didn’t look like they had a [treatment] option [based on the results of their] original testing. For these patients, some of the earlier hotspot panels do not include testing for all of these targets. It’s important to look back as these new drugs become available to see whether additional testing is needed to [identify] more options for these patients.

We’re seeing a number of advances being made in the metastatic setting with immunotherapy and targeted therapy being evaluated for patients with earlier-stage [disease], particularly curative-intent treatment options. This is important because when we talk about curative-intent treatment, we know that the risk of relapse for patients with stage II and III lung cancer is still quite high. Seeing these advances moving into those disease stages will give us an opportunity to improve outcomes for patients with earlier-stage disease as well.

Are there specific clinical trials that could further the field of precision medicine in advanced NSCLC?

We are going to see the outcomes of a few clinical trials over the next few years that could help us guide therapy further. We have all the ongoing studies [evaluating] KRAS [G12C] inhibitors, which will be helpful.

A number of clinical trials are also looking at incorporation of neoadjuvant and adjuvant treatments for NSCLC using immunotherapy and molecularly targeted therapy. Those studies will be interesting to watch.

Again, we are watching these therapies move into the earlier-stage settings. In the very short-term future, the results of the IMpower010 study [NCT02486718], evaluating the use of adjuvant consolidative atezolizumab [Tecentriq] following definitive therapy for stage II and III NSCLC, are expected soon. [The data] are reported to be positive at least per press releases. [Those data will give us] a better understanding of whether [adjuvant atezolizumab] is something we will be using in the near future.

Are there other nuances to your treatment approach for patients with advanced NSCLC that you would like to highlight?

One additional point is about access to clinical trials. Our standard-of-care options are improving rapidly for patients with lung cancer, but we still have quite a lot of room for improvement. I always encourage early involvement in a center that offers clinical trial options for patients. We can try to pair patients with a trial if they are eligible and interested in participating.

Another point I would like to add is that when we think about advanced NSCLC, it is important to keep an eye out for patients with oligometastatic or oligoprogressive disease. All forms of disease presentation and progression may not require initiation of or change in systemic therapy. For example, keep an eye out for patients with limited sites of metastatic disease or central nervous system–only metastatic disease at presentation because they may be eligible for a more aggressive treatment strategy involving definitive therapy to all areas of disease.

In patients with oligoprogressive disease, there may be a role for a definitive local therapy to limited sites of resistance, which will allow a patient to continue benefitting from existing therapy for a longer period of time.