Research Prevails in NSCLC Despite the Challenges Wrought by COVID-19

Findings from the phase 3 ALEX trial demonstrated the attainability of achieving long-term survival in patients with oncogene-driven advanced non–small cell lung cancer (NSCLC), explained Ullas Batra, MBBS, MD, DM, who added that subsequent findings from the adjuvant ADAURA and neoadjuvant immunotherapy trials have the potential to double survivorship by 2025.

“2020 was a very devastating year as far as COVID-19 and cancer is concerned, but even over the past year, thoracic oncology researchers have been doing what they did for the past 20 years––that is, give hope to the patients and add life to their years,” said Batra.

In an interview with OncLive, Batra, senior consultant and chief of thoracic medical oncology at the Rajiv Gandhi Cancer Institute and Research Centre, in New Delhi, India, discussed the durability of targeted therapy in advanced NSCLC and the movement of targeted therapy and immunotherapy into earlier stages of disease.

OncLive:How has the field of thoracic oncology evolved over the past year?

Batra:The proportion of patients with long-term lung cancer survival has increased based on the data from the neoadjuvant trials and the ADAURA study in early-stage lung cancer. Even in stage IV cancer, the ALEX data showed a 5-year survival [rate] of 62.8%. The CROWN data [are also impressive]. Long-term lung cancer survival has increased, and that is the biggest takeaway of 2020.

What were your initial thoughts on the ADAURA data?

My first reaction was: Wow. [All you have to do is] look at the [disease-free survival] curves and look at the difference [between the arms]. There will always be naysayers and pessimists, but [osimertinib (Tagrisso)] is an option that needs to be discussed with the patient because we do not want to be playing catch up. Now in COVID-19, we are playing the catching up game. Let’s vaccinate everyone [instead. Similarly], let’s give everyone the option of osimertinib and let the disease go behind us instead of being behind the disease.

In terms of the 5-year data from the ALEX trial, did you ever think that we would get to a point where the majority of patients are reaching that 5-year benchmark with an oral agent?

No, not at all. When I finished my fellowship in 2007, there was no EGFR[-targeted agent]. EGFR had just come in, and there was no pemetrexed. There was no ALK[-targeted agent either].

A 5-year survival [rate] of 62.8% or close to it in stage IV disease with an oral drug [was] unheard of. However, we always want more. Hopefully, [we’ll be] looking at 10-year survival [rates] now. The aim is to double lung cancer survivorship by 2025.

Do checkpoint inhibitors have the potential to make chemotherapy irrelevant in lung cancer?

I don’t think so. Chemotherapy has been the workhorse of lung cancer for the past 40 years. Even though we have made huge strides in the management of lung cancer with immunotherapy and targeted therapy, the agents are prohibitively expensive.

Let’s think about patients with PD-L1 expression of more than 50%. Solange Peters[, MD, PhD, of the University of Lausanne,] presented data at the 2020 ESMO Congress in nonsmokers with PD-L1 expression of more than 50%, [showing that] immunotherapy alone is not good enough.

What about patients who have PD-L1 expression of 0% to 49%? You will either have to give them a KEYNOTE-189 regimen or you will have to give them a CheckMate 9LA regimen. I don’t think immunotherapy or targeted therapy will replace chemotherapy; they will instead work in tandem. The pie chart of chemotherapy may reduce, but it’s not really going to go away, especially not in developing countries.

Were there any other important studies that came out within the past year that you want to highlight?

One of the huge improvements to me was immunotherapy in the neoadjuvant setting. When it comes to early-stage lung cancer, we’re [not impressed by a] 5% survival difference. However, neoadjuvant chemoimmunotherapy increases major pathological response rates, which has the potential of leading to long-term survival.

Stage I/II breast cancer has a survival [rate] of 90% to 95%. A stage I/II lung cancer does not have that survival. Although immunotherapy is important in the stage IV [setting], it’s also going to be important in stage I/II and III lung cancer.

In advanced NSCLC, the KRAS inhibitor sotorasib [is exciting]. The KRAS oncogene was found on many next-generation sequencing [tests] we did, and now we have oral treatment available for [patients with KRAS G12C mutations], which is a huge improvement [from the historical standard].

The CROWN study also caught our attention. One single drug, if it is able to show a good progression-free survival [PFS] and overall survival [OS] advantage, will probably elevate the need for re-biopsies, and maybe a single drug will take care of all the ALK inhibitors, with hopefully a 7- or 10-year survival [expectancy].

In terms of newer targeted agents, we’re seeing some significant toxicity. Are the on- or off- target adverse effects (AEs) associated with some of these agents cause for concern? How can we understand their risk-benefit profile?

We need to understand why these targeted therapies were developed. Previously, the World Conference on Lung Cancer used to happen once every 2 years, and now we are having a bunch of [lung-focused conferences]. Targeted therapies have revolutionized the treatment of lung cancer, but everything comes at a cost. The cost here that we pay is the toxicity. Each drug has a unique AE profile. Just because they’re oral drugs, [that doesn’t mean] nothing will happen [in terms of toxicity].

With regard to ALK inhibitors, crizotinib [Xalkori] has a different AE profile than ceritinib [Zykadia]. Lorlatinib [Lorbrena] has triglyceridemia, weight gain, and neuropsychiatric characterization. All ALK inhibitors are not the same. The physician should be aware, the oncologist should be aware, and the patient should be aware, because a well-informed patient is the best patient.

On a research level, more emphasis should be placed [on patient education]. We always talk about the PFS and OS advantage. What about the quality of life [QOL] and health-related QOL? These [parameters] need to be emphasized and [reported] in as much of a stern language as PFS and OS. Real-world data and phase 4 data also need to be published and discussed more, because not all my patients have an ECOG performance status [PS] of 0 or 1.

What ongoing or planned studies are you particularly excited about?

From a diagnostic point of view, liquid biopsy has the potential to be tapped. We have only [reached] 20% of its potential. [What about] screening, diagnosis, and the dynamic monitoring by liquid biopsy to assess minimal residual disease?

With regard to ADAURA, does everyone need 2 or 3 years of osimertinib? Liquid biopsy is something that I’m really interested in [as a way to answer that question].

As far as therapeutics are concerned, neoadjuvant and adjuvant therapy and KRAS inhibitors are very important. Even though we have made huge strides in the management of lung cancer, still, only 40% of patients respond, so mechanisms of primary resistance and acquired resistance are the things to be understood, and that is what I’m looking at in the coming year.