NSCLC Paradigm Progresses With Adjuvant Treatment and Overcoming Resistance

Rodolfo Bordoni, MD

As the armamentarium of advanced non–small cell lung cancer (NSCLC) continues to grow with the addition of novel targeted therapies for rare subtypes, the field is simultaneously shifting to evaluate targeted therapy and immunotherapy in earlier lines of treatment, including the neoadjuvant and adjuvant spaces, said Rodolfo Bordoni, MD. He added that these settings represent areas of significant clinical research that could further improve outcomes for patients.

“For the past 15 years in lung cancer, we have been spending all of our energy in advanced disease. Now [the goal is] moving [our efforts] to early-stage disease where we are seeing the same or even better success with interventions,” said Bordoni in an interview with OncLive^® during an Institutional Perspectives in Cancer (IPC) webinar on lung cancer that he chaired.

In the interview, Bordoni, a medical oncologist, director of Clinical Research and leader of the phase 1 clinical trials program at Georgia Cancer Specialists in Atlanta, discussed updates with adjuvant therapy in NSCLC, overcoming resistance to ALK inhibitors, and the importance of nextgeneration sequencing (NGS) in the lung cancer paradigm.

OncLive®: Based on the results of the phase 3 ADAURA trial (NCT02511106), should patients with resected EGFR-mutated NSCLC receive chemotherapy before adjuvant osimertinib (Tagrisso)?

Bordoni: [In the ADAURA trial], patients with early-stage lung cancer after complete resection were treated with a third-generation EGFR TKI [tyrosine kinase inhibitor] in the adjuvant setting. [Approximately] 75% of patients received adjuvant chemotherapy before the EGFR TKI; the rest of the patients went directly into the allocation between [osimertinib] or placebo. 

[Patient stratification should allow us] to advise the patients to receive chemotherapy before the TKI; however, that is still a gray area and an opportunity for improvement.

What is the current state of neoadjuvant treatment for patients with NSCLC?

One of the areas in early-stage disease that I have been interested in for many years is neoadjuvant therapy. There now seems to be a revival of this modality. We knew about chemotherapy in the neoadjuvant setting and, more recently, immunotherapy became a very interesting proposal. Targeted therapy [is also possible in the neoadjuvant setting] for a short period of time before the patient goes for definitive surgery. 

In our network, we are conducting a neoadjuvant [study] to evaluate chemoimmunotherapy vs chemotherapy, which is the standard of care still. However, a significant amount of data has been mounting for the past 3 or 4 years since Dr Patrick Forde’s publication in the New England Journal of Medicine. This is an area of active research that is going to add to the adjuvant setting. [Neoadjuvant therapy] will be the intervention we use before and even after surgery as a maintenance approach. All areas of intense research, including multimodality therapies, [are exciting] for earlystage lung cancer.

How has the standard of care changed for patients with NSCLC in need of adjuvant therapy?

Until 2019, the standard of care for this population was just chemotherapy. A couple of clinical trials [were ongoing]. A few of them were successful, some of them were not, [including] some that evaluated targeted therapy plus or minus chemotherapy. The problem [with those negative trials] was probably the selection of the patients. 

Therefore, the standard of care was adjuvant chemotherapy or observation according to TNM [tumor, lymph nodes, metastasis] staging of the patient.

More recently, atezolizumab [(Tecentriq) was shown to be] efficacious when used in the adjuvant setting for patients who receive a complete resection of the tumor and require some form of adjuvant therapy, as long as the cancer cells express PD-L1. That is critical. Patients without PD-L1 expression were not responders and the intervention was not successful. 

[Although] the FDA approval [of atezolizumab] was very recent in October 2021, [the adjuvant setting] is an area that we will continue to learn about. Several clinical trials are being conducted with immunotherapy alone or in combination with, for instance, chemotherapy. Further data are awaited, and we will probably have that data in the next 2 years.

During the IPC meeting, Ticiana Leal, MD, of Winship Cancer Institute and Emory University School of Medicine, further discussed the role of adjuvant treatment in NSCLC. Could you expand on the significance of the FDA approval of adjuvant atezolizumab in NSCLC?

One of the reasons why the approval of atezolizumab is exciting and important is because until now the only option for the patients who had to receive adjuvant treatment after surgery was chemotherapy. Of course, we now have targeted therapy, but remember that applies to a very small population of patients. In the Caucasian population, it may be 14% or 15% of patients, and some people in Europe believe it is up to 17% of patients [that harbor] EGFR exon 19 [deletions] and exon 21 mutations. In Asia, it is 40% to 50% of patients who are mainly female non-smokers. Therefore, for all those patients, [we can] apply targeted therapy after surgery. 

However, there is a huge population of [unmutated] patients that are not fit to receive chemotherapy. If they are fit, [we wanted to see] if there was any way we could save those patients from the toxicity [of chemotherapy]. Usually when we talk about chemotherapy toxicity, we think acute [toxicities] that go away in 4 months; however, in some patients they don’t. Some patients are left with renal insufficiency, peripheral neuropathy, or cytopenias. [Cytopenic events] are usually [not] clinically relevant, [but it is still a toxicity], nonetheless.

That is why the [approval of atezolizumab] is so relevant because of the wide implications for a high number of patients. It is very effective and can save patients [from experiencing added toxicity].

Josephine Louella Feliciano, MD, of Johns Hopkins Medicine, talked about frontline immunotherapy options in metastatic NSCLC. How have dual immunotherapy strategies changed the landscape of NSCLC?

We are familiar with dual immunotherapy in advanced diseases, but mainly in metastatic melanoma. We understand that patients with lung cancer are not the same as those with melanoma. Patients with melanoma, in general, are [similar to] patients with breast cancer in that they are healthy except for the cancer. Therefore, they can tolerate aggressive therapies that are toxic to some extent, including dual immunotherapy. Patients with lung cancer are usually sicker and have many comorbid conditions [that make] the addition of ipilimumab [(Yervoy) to treatment difficult].

However, we have found that [adding ipilimumab to treatment] is an option, but it was a matter of learning how to use the combination of nivolumab [Opdivo] and ipilimumab and how to manage, even preemptively, some of the immune-related adverse effects. Now we have extended experience [with the dual immunotherapy combination]; the follow-up is now 4 years. We still see significant and sustained benefit [from nivolumab/ipilimumab] in those patients. Dual immunotherapy as a first-line treatment for patients with advanced lung cancer is here to stay.

One of the questions Dr Feliciano presented to the audience [during the IPC meeting] was whether the combination [of nivolumab and ipilimumab], as well as the CheckMate 9LA [NCT03215706] combination of nivolumab, ipilimumab, and a short, 2-cycle intervention of chemotherapy, applies to patients with PD-L1–negative tumor expression. My personal take is that, yes, dual immunotherapy plus or minus short-term chemotherapy should apply to patients with PD-L1–negative disease. However, again, because the intent of the trial was mainly for patients with PD-L1–positive disease, some [clinicians] believe we have to be cautious with the indication in PD-L1–negative patients.

Tejas Patil, MD, of the University of Colorado Medicine, highlighted new strategies in the management of patients with ALK-positive metastatic NSCLC. How do you approach treating patients who develop resistance to frontline ALK inhibitors?

Many people believe that if the patient was treated initially with a first-generation ALK inhibitor, it is just a matter of moving to second- and third-generation ALK inhibitors. Finally, if nothing is left, we can go to chemotherapy or chemoimmunotherapy. That has been shown for quite a while; however, clinical trials are still ongoing that are showing that is not the case. The best way to treat patients with ALK-positive disease is that, upon progression on an ALK inhibitor, [we should] try to understand the mechanism of resistance. Based on that, for some patients, we move to [a second- or third-generation inhibitor] most of the time. However, in some patients, we have to move to the left [with another first-generation inhibitor] to obtain the maximum benefit from a therapeutic standpoint. It’s important to understand the mechanism of resistance and evaluate for those mechanisms before moving on to the next treatment.

Also, sometimes when patients progress on ALK inhibitors, it is not a matter of using another ALK inhibitor. Maybe those patients have a mutation that is very difficult to treat with an ALK TKI. Unfortunately, we need to treat with chemotherapy or chemoimmunotherapy. Even some chemotherapies are for different histologies, [such as] in small cell lung cancer.

Finally, Ignacio I. Wistuba, MD, of The University of Texas MD Anderson Cancer Center, talked about biomarker updates in NSCLC. With the significant advances we saw regarding targeted therapy in 2021, could you speak to the importance of obtaining NGS for patients?

A few years ago, the National Comprehensive Cancer Network came up with 4 biomarkers that we must test for. More recently, [these were increased to] 9 [biomarkers] in addition to PD-L1. NGS checks for many more genes, and some of these tests apply to hundreds of genes. The reason is not only to guide treatment but also for discovery of new treatments.

Dr Wistuba concentrated on a couple [actionable alterations]. One of them was KRAS G12C, which is [found in] about 12% to 13% of the squamous and nonsquamous NSCLC patient populations. Finally, we have an effective [agent] that is a specific KRAS inhibitor [with sotorasib (Lumakras)]. The disease-free survival with that agent is around 6 months. Some people may believe that 6 months is not that significant, but for patients who progress on chemotherapy in a matter of weeks, 6 months becomes significant. Even more, we must consider that sotorasib provides a time to progression of about 1 year and an overall survival above 12 months. 

HER2—we try not to call it HER2 anymore, but instead ERBB2—is very common in patients with breast cancer but has now become important in lung cancer. The incidence [of ERBB2 mutations] in lung cancer is not that high, maybe less than 5%, but for those patients carrying a HER2 insertion mutation in exon 20, there are good treatment options that we didn’t have before. 

What other advances from 2021 stood out to you as being potentially practice changing?

Something that was remarkable and worth a presentation by the FDA at the last committee [meeting] was the pooled analysis of patients with PD-L1 expression between 1% and 49%. That has been a gray [area] until now. [The FDA] specifically concentrated on that population and evaluated what the best treatment option is for those patients. Should those patients be treated with single-agent immunotherapy or chemoimmunotherapy? [The presentation showed] with statistical significance that for patients with less than 50% PD-L1 expression, single-agent immunotherapy is probably not the best option...and they should be offered chemoimmunotherapy. Even more, the conclusions of that presentation were that for future clinical trials randomizing patients between immunotherapy and chemoimmunotherapy, this pooled analysis should be taken into consideration. That changed my view of the approach in that group of patients. This retrospective exploration shed light on a group of patients we were struggling with [treating] until now, so that was a highlight of the meeting.