TKIs, Immunotherapy, and ADCs Amplify the SCLC and NSCLC Treatment Paradigms

Millie Das, MD

The immunotherapy armamentarium continues to expand for patients with non–small cell lung cancer (NSCLC), although further research is needed to determine the optimal combinations for individual patients, according to Millie Das, MD. Additionally, the field of small cell lung cancer (SCLC) management has evolved to include novel chemotherapy and immunotherapy options.

"It was a pleasure to be able to chair this event and to be there with my colleagues, providing some education to our teams about how we can think about some of the drugs and trials that are being completed in the treatment of patients with lung cancer, with the ultimate goal of providing better outcomes for them," Das said in an interview with OncLive® following a State of the Science Summit™ (SOSS) on lung cancer, which she chaired.

In the interview, Das highlighted key points that were presented at the meeting, including early efficacy signals with PARP inhibitors in patients with SCLC, how overall survival (OS) data from the phase 3 ADAURA trial (NCT02511106) confirm the efficacy of adjuvant osimertinib (Tagrisso) in patients with NSCLC, and which patients may benefit most from immunotherapy as monotherapy or in combination with other agents. 

Das is a clinical associate professor of medicine-oncology and a member of Stanford Cancer Institute, as well as the associate program director of Oncology Fellowship at Stanford University and chief of Oncology at VA Palo Alto Health Care System, all in California.

OncLive: Why is chemoimmunotherapy the first-line standard of care for patients with SCLC? How has this affected second-line sequencing?

Das: For patients with extensive-stage [ES]-SCLC, we are now using immunotherapy in combination with platinum/etoposide as part of frontline treatment. This is based upon [data from] randomized phase 3 trials that showed an approximate 2-month survival benefit with the addition of either atezolizumab [Tecentriq] or durvalumab [Imfinzi], to platinum/etoposide. This is now our current standard. This is a regimen we’re offering to our patients with ES- SCLC, who will go on to receive maintenance immunotherapy as well.

At the time of disease progression, usually on maintenance immunotherapy, we have second-line options available for patients. For the longest time, the only FDA-approved option was topotecan, so many of us were using either topotecan or irinotecan in the second line. As of June 2020, the FDA provided accelerated approval for lurbinectedin [Zepzelca] in patients with relapsed SCLC, so that is now another option we can offer patients. There are now many other emerging therapies in the second line, which we’re looking forward to hearing more about.

What treatment approaches are on the horizon for patients with SCLC?

At some recent conferences, we’ve heard data regarding PARP inhibitors in combination with temozolomide, where we’re seeing an overall response rate of 39.3%. The data we have so far are encouraging. [This combination is] being explored in larger-phase trials. There’s also much excitement about DLL3-targeting T-cell engagers. Several different companies are now testing this strategy in patients with relapsed SCLC, and larger studies in patients with SCLC are underway. 

What should oncologists know about treating veterans with SCLC?

As an oncologist who takes care of veterans at a VA facility, I’ve noticed differences between veteran and non-veteran patient populations. Veterans tend to have a higher incidence of smoking-related malignancies, including lung cancer. Oftentimes, they present with multiple comorbidities linked to their smoking, such as cardiovascular disease or stroke. It’s common that we need to comanage these patients with other medical subspecialists.

Sometimes, these comorbidities come into play as we’re thinking about treatment options for patients. Many patients may have underlying chronic kidney disease or underlying poor performance status from having had a stroke or a heart attack in the past. These are factors we need to keep in mind as we’re prescribing treatments. Veterans also, in my experience, tend to present with more advanced disease. That can make it more challenging to treat these patients.

One of the things the VA does well is, because we’re an integrated health care system, endorsing and ensuring that eligible patients undergo low-dose computed tomography screening. Our screening rates within the VA are higher than the screening rates in the community. The hope is, as we continue to screen more high-risk individuals, we will be able to detect lung cancer at an earlier stage, intervene earlier, and ultimately provide better outcomes for these patients.

Regarding the presentation by Mohana Roy, MD, of Stanford University, on updates in EGFR-positive lung cancer, where might osimertinib fit into the EGFR-mutant NSCLC treatment landscape?

Dr Roy did a great job presenting the landscape of EGFR-positive NSCLC. We saw the FDA approval of the third-generation EGFR TKI osimertinib [in the front line for patients with EGFR-positive NSCLC], based on data from the [phase 3] FLAURA trial [NCT02296125] data. This is now the preferred frontline approach for patients with EGFR sensitizing mutations.

More recently, we saw data come out from the ADAURA trial looking at adjuvant osimertinib in patients with early-stage resected disease with EGFR mutations. The exciting data that were presented at the 2023 ASCO Annual Meeting were the OS data from ADAURA. Not surprisingly, we saw a significant OS benefit in patients who received 3 years of adjuvant osimertinib compared with placebo. Based upon the significant disease-free survival benefit with osimertinib that was previously presented, the FDA approved this as an option [in patients with resected EGFR-positive NSCLC]. The OS data that were presented [at ASCO] reinforce the use of osimertinib as an adjuvant treatment option for patients with resected, EGFR-positive lung cancer.

Joel Neal, MD, PhD, of Stanford Cancer Institute, discussed antibody-drug conjugates (ADCs), bispecific antibodies, and novel immunotherapies in patients with lung cancer. What does the future look like for ADCs in the lung cancer treatment paradigm?

Dr Neal provided an elegant presentation of novel treatments, including bispecific antibodies and ADCs. Many of these drugs are being used across disease types, not just in lung cancer. We’ve seen approvals of ADCs in other cancer types, such as breast cancer and some genitourinary malignancies.

We’re starting to see these drugs in clinical trials in lung cancer, and they’re showing significant promise. Over the upcoming years, we will start to use these drugs more in the treatment of patients with lung cancer. It was great to learn about these novel treatment strategies that will be entering the treatment arena for patients with lung cancer.

Regarding the presentation by Kavitha Ramchandran, MD, of Stanford Cancer Center on supportive care tactics in lung cancer, what is the importance of considering the emetogenicity of individual chemotherapy regimens?

Dr Ramchandran wears 2 hats. She’s a thoracic oncologist and a palliative care specialist. I appreciated her talking about something we all deal with on a frequent basis when prescribing chemotherapy to patients: chemotherapy-induced nausea/vomiting. [Dr Ramchandran discussed] current treatments we can offer to patients based upon the emetogenicity of the regimen we’re prescribing.

[Chemotherapy agents] have unique adverse effects to be aware of. Each of these drugs is usually [categorized] by its emetogenic potential: high, moderate, low, and very low. [Dr Ramchandran outlined] some of the strategies we use based upon the emetogenic potential [of each chemotherapy regimen]. It was useful to think about the chemotherapies that we prescribe in that way and think about the optimal anti-emetics we should prescribe to patients.

Heather Wakelee, MD, of Stanford Cancer Institute, presented about immunotherapies in NSCLC. Where might perioperative pembrolizumab {Keytruda) play a role in this population?

Dr Wakelee [discussed] many of the different perioperative [treatment approaches] in lung cancer, including data from the [phase 3] KEYNOTE-671 clinical trial [(NCT03425643), results from which were published in August 2023], whereby patients received pembrolizumab in combination with chemotherapy neoadjuvantly [followed by] additional adjuvant pembrolizumab. This trial was a bit different from the [phase 3] CheckMate 816 study [NCT02998528] where patients received nivolumab [Opdivo] in combination with chemotherapy neoadjuvantly. There was no adjuvant portion to that trial.

The data we have from the KEYNOTE-671 trial show a significant event-free survival benefit in patients who received pembrolizumab. We’re awaiting an FDA approval for [perioperative pembrolizumab in patients with NSCLC]. However, this adds to some of the data we have for immunotherapy in the perioperative setting for patients with lung cancer. [We should] try to understand the benefit of additional adjuvant immunotherapy. Perhaps not all patients will benefit. [It is important] to figure out strategies of individualizing some of these treatment decisions, including measurement of circulating tumor DNA [ctDNA]. Dr Wakelee spoke to that as well, as we’re trying to come up with commercial assays that will be reliable in detecting ctDNA in the blood.

Regarding the presentation by Nathaniel Myall, MD, on immunotherapy in advanced/metastatic NSCLC, what research supports the use of dual checkpoint inhibition with CTLA-4 and PD-L1 inhibitors in this population?

Dr Myall did a great job talking about the many studies in the advanced or metastatic NSCLC setting, [including trials investigating] immunotherapy in combination with chemotherapy, immunotherapy alone, and dual checkpoint inhibitors. [He discussed] data from the [phase 3] CheckMate-227 trial [NCT02477826]investigating ipilimumab [Yervoy] plus nivolumab and the [phase 3] POSEIDON trial [NCT03164616] investigating the combination of durvalumab and tremelimumab [Imjudo]. In POSEIDON, durvalumab and tremelimumab were combined with chemotherapy. [Dr Myall] put these trials into context with some of the other immunotherapy trials to try to understand which patients are most likely to benefit from the different treatment strategies.

[Another] point made by Dr Myall was that perhaps patients with PD-L1–negative disease would benefit most from dual checkpoint inhibition, particularly the ipilimumab/nivolumab combination, or potentially the POSEIDON regimen of durvalumab/tremelimumab plus chemotherapy. We’re still trying to understand which patients are most likely to need or benefit from combined immunotherapy, but [the PD-L1–negative population] seems to be a patient population where we’re thinking it may be of greatest use.

What lung cancer research is ongoing at Stanford?

We have [phase 2 (NCT04310007) and phase 3 (NCT04585490) ctDNA trials at Stanford. These are being led by Drs Neal and Maxilimian Diehn, MD, PhD, [of Stanford University], in patients [with NSCLC] who are being treated definitively with [immunotherapy, chemotherapy], radiation, or a combination of chemoradiation, and will then undergo ctDNA measurements.

[In the phase 3 trial, patients are] allocated to different treatment arms based upon whether they have positive or negative ctDNA [results]. This is an exciting trial because its goal is to try to individualize treatment decisions based upon whether patients have ctDNA. Patients with ctDNA have a high risk of recurrence and potentially [worse outcomes], so, is there a way we can intervene early to try to improve outcomes for these patients? We’re actively accruing to these ctDNA trials.

What is your main message for colleagues regarding this SOSS?

I appreciated the ability for all of us to get together to talk about some of these highlights in lung cancer. There are frequent FDA approvals and data that are getting published. It was useful for all of us to come together to talk about some of the data that were presented at conferences in the past year or 2 and to try to put those data into context of how we care for patients. I look forward to future events like this.

Disclosures: Dr Das reports research grants from Genentech, Merck, CellSight, Novartis, and Varian; a consulting position with Eurofins; and advisory roles with Sanofi/Genzyme, Beigene, Regeneron, AstraZeneca, Janssen, and Gilead.