Landmark Studies Propel Lung Cancer Treatment Forward

Aakash Desai, MD, MPH

A surge of interesting data in the lung cancer space came from the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. According to Aakash Desai, MD, MPH, some experts have even referred to the meeting ASCO Lung instead of ASCO 2024.

“We are excited to see a lot of progress being made in lung cancer, it being one of the cancers with the highest mortality,” Desai, thoracic and phase 1 medical oncologist and assistant professor at the O’Neal Cancer Center at the University of Alabama, Birmingham, told Targeted Oncology^TM, in an interview.

One theme of interest from the meeting was the use of targeted therapies, particularly for patients with oncogene-driven non–small cell lung cancer (NSCLC), and data from trials like PACIFIC (NCT02125461), LAURA (NCT03521154), CROWN (NCT03052608), and more have paved the way to new and potential therapeutic for lung cancer treatment.^1,2,3

Desai also noted the promising results from the ADRIATIC study (NCT03703297) in limited-stage small cell lung cancer (SCLC) where, at a median follow-up of 37.2 months (range, 0.1-60.9), the median overall survival observed among patients treated with durvalumab (Imfinzi; n = 264) was 55.9 months (95% CI, 37.3-not evaluable) compared with 33.4 months (95% CI, 25.5-39.9) for those given placebo (n = 266), translating to a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.57-0.93; P = .0104).⁴

In the interview, Desai discussed significant lung cancer treatment advancements that were highlighted at ASCO 2024, particularly in targeted therapies for NSCLC and new treatment strategies for limited-stage SCLC.

Targeted Oncology: What were some of the overall themes or areas of greatest progress reflected in the research presented at ASCO 2024?

Desai: At ASCO this year, we saw a lot of interesting abstracts and presentations around lung cancer. In our oncology community, there was a discussion whether this was ASCO Lung instead of ASCO 2024. We are excited to see a lot of progress being made in lung cancer, it being one of the cancers with the highest mortality. Among those, the theme that emerged was targeted therapy, especially for the oncogene-driven non–small cell lung cancer. We also had our first sort of advance in small cell lung cancer, especially for the limited stage, in many years, a couple of decades, actually. [I am] excited to see all the progress and some of these being already incorporated into clinical practice.

Lungs © Mopic - stock.adobe.com

Can you highlight a few of those interesting lung abstracts encountered?

Two of them actually made the plenary, so I'll talk about those first. The first was within the EGFR space for [patients with] unresectable, stage III non–small cell lung cancer who undergo definitive chemoradiotherapy. Pre-ASCO, we did not have a lot of data on what to do for those patients who have an EGFR mutation and end up being diagnosed with stage III unresectable non–small cell lung cancer. The typical approach was based on the PACIFIC study [NCT02125461] where you give chemoradiation followed by durvalumab as a consolidation treatment.

There was some concern that durvalumab may not be an efficacious treatment strategy specifically for the oncogene-driven subset like EGFR, so the LAURA study was a phase 3 trial that tested osimertinib [Tagrisso] after definitive chemoradiotherapy in patients with unresectable, stage III, EGFR-mutated non–small cell lung cancer. Essentially, the study design randomized patients to osimertinib 80 mg per day vs placebo following definitive chemoradiation. What we found was the median [progression-free survival (PFS)]with osimertinib was 39.1 months compared [with] 5.6 months with placebo, a huge benefit in terms of median progression-free survival. The overall survival results were presented, but they were not mature at the time. I think this is enough robust evidence for me to incorporate this into my clinical practice, in terms of the patients that I see with EGFR-mutated non–small cell lung cancer and stage III.

What should a community oncologist know about this research?

A community oncologist should understand the importance of testing for these oncogenes in non–small cell lung cancer tumors, even in stage III. It has been common practice in stage IV for a few years now, and we are increasingly seeing with this study and other studies in the early-stage setting for resected non–small cell lung cancer that testing for oncogene drivers is becoming increasingly important because we do not want to miss an opportunity if we can put a patient on a pill to treat that lung cancer rather than have them come in for infusions every 3 weeks. Also, the [adverse] effect profile is quite different. It does have its own set of [adverse] effects, but again, nowhere close to being as toxic or as difficult to tolerate as chemotherapy is. I think it is important for us to make sure that we are testing all our patients for these oncogene drivers.

What were some other updates in the targeted therapy space that you could highlight?

There was a 5-year update from the CROWN study for the ALK-positive non–small cell lung cancer, which compared lorlatinib [Lorbrena] with crizotinib [Xalkori]. We saw again, the median progression-free survival with lorlatinib was not reached compared with 9.1 months with crizotinib. Again, we saw that at 5 years, 60% of patients were surviving with lorlatinib vs 8% with crizotinib. So again, a huge difference. I think this is some of the best data that we have in this ALK-positive non–small cell lung cancer space. Again, it kind of solidifies the fact that first-line lorlatinib continues to demonstrate sustained systemic, as well as [central nervous system (CNS)] efficacy with no new safety signals. This was more of a practice-conforming treatment strategy trial. The update confirms what we think should be the standard of care in the first line with lorlatinib.

There were some other interesting studies as well. Specifically, the PALOMA-3 study [NCT01942135] which introduced a different formulation of a drug that we commonly use in practice called amivantamab-vmjw [Rybrevant] for EGFR-mutated non–small cell lung cancer. They compared subcutaneous vs intravenous [IV] amivantamab in this particular study. Again, it was a phase 3 study looking at locally advanced or metastatic non–small cell lung cancer with the common EGFR mutations and randomized patients with subcutaneous amivantamab plus lazertinib [Leclaza] vs intravenous amivantamab plus lazertinib. They discussed really good results from a pharmacokinetic standpoint, area under the curve and such, basically showing that subcutaneous is as good as IV in terms of the pharmacokinetics of the drug. Also, some of the results that they presented in terms of median progression-free survival were comparable, if not better with the subcutaneous.

We saw that the adverse events with subcutaneous were much less in terms of the infusion-related adverse events, as well as any other grade 3 adverse events that we saw. Again, encouraging, and I think this is going to be practice changing. Intravenous has a lot of logistical challenges in terms of clinic infusion times, as well as time toxicity for patients, spending a few hours of the day in the infusion clinic vs having a subcutaneous option, which is going to be much faster in terms of time. So, a good advance for our patients.

Can you further discuss the ADRIATIC study in SCLC?

I think this has changed and will change clinical practice once it is approved. The ADRIATIC study studied durvalumab as consolidation treatment for patients with limited-stage small cell lung cancer. Patients with limited-stage small cell lung cancer currently get chemoradiation without any consolidative treatment. This has been sort of the standard of care for a couple of decades. With this particular study, they did look at overall survival as a dual primary end point, but also PFS. We did see that the median PFS was improved with durvalumab at 16.6 vs 9.2 months. In terms of the [overall survival], we also saw median overall survival benefit with durvalumab at 55 months vs 33 with placebo. I think this is an important advance, especially for small cell lung cancer, which is a very difficult to treat disease and an aggressive disease. For those patients with limited-stage SCLC, the option of incorporating immunotherapy and the outcomes and efficacy that we see is exciting, and I definitely will use it in the clinic once it is approved.

What are some of the next steps for these promising studies that you saw?

We have good evidence now based on trials. I think we need to see how these perform in the real world and how we incorporate them into the real world. I think the benefits that we are seeing on the trials does make sense for us to be readily implementing them in the clinics, but we know from other studies and previous research that real-world practices may differ, so we need to make sure that these practices conform more to the guidelines and the evidence that we have.

What unmet needs still exist in this space?

I think the unmet need, especially for the non-oncogene-driven advanced non–small cell lung cancer, in the second-line space is still an unmet need. We were excited for the presentation on 1 of the antibody-drug conjugates, sacituzumab govitecan-hziy [Trodelvy], which they compared with docetaxel in the EVOKE-01 study [NCT05089734], which was a phase 3 study. Unfortunately, that study did not show any superiority in terms of overall survival with antibody-drug conjugates compared with docetaxel treatment that is currently standard of care and used in clinics. We were hoping that this would be a good advance for our patients and that we would have another option to offer, especially because the patients who have tumors which are refractory or relapsed after immunotherapy and chemotherapy are typically difficult to treat. Unfortunately, I think this still remains an unmet need in this space where we do not readily have any option available except for the docetaxel that we have been using for decades.

Are there any upcoming or ongoing clinical trials investigating new therapies that you find interesting?

There are a few in terms of newer antibody-drug conjugates, as well as bispecific antibodies. As I mentioned, the sacituzumab govitecan TROP2 antibody-drug conjugate trials did not pan out, but we have some data from datopotamab deruxtecan [DS-1062a; Dato-DXd], which is a different antibody-drug conjugate using the same tumor associated antigen, which does have some positive signal. I think it remains to be seen how this is read by the FDA, and whether this is approved or not. Regardless, there is a lot of excitement in the field for these antibody-based therapies.

There is another bispecific antibody ivonescimab [SMT112] and some data presented at ASCO [that was] conducted in China and was encouraging in the EGFR post-osimertinib settings. Again, as these studies become global and we get more data from these studies, I am excited for the potential of these antibody-based therapies to change and improve outcomes for our patients with non–small cell lung cancer.

REFERENCES:

1. Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous amivantamab vs intravenous amivantamab, both in combination with lazertinib, in refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results, including overall survival (OS), from the global, phase 3, randomized controlled PALOMA-3 trial. J Clin Oncol. 2024;42(suppl 17):LBA8505. doi:10.1200/JCO.2024.42.17_suppl.LBA8505

2. Ramalingam SS, Kato T, Dong X, et al. Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: primary results of the phase 3 LAURA study. J Clin Oncol. 2024;42(suppl 17):LBA4. doi:10.1200/JCO.2024.42.17_suppl.LBA4

3. Solomon BJ, Liu G, Felip E, et al. Lorlatinib vs crizotinib in treatment-naïve patients with advanced ALK+ non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study. J Clin Oncol. 2024;42(suppl 17):LBA8503. doi:10.1200/JCO.24.00581

4. Spigel DR, Cheng Y, Cho BC, et al. ADRIATIC: durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). J Clin Oncol. 2024;42(suppl 17):LBA5. doi:10.1200/JCO.2024.42.17_suppl.LBA5