Garon Discusses the Standing and Future of ADCs, Targeted Therapies in NSCLC

As patients with non–small cell lung cancer (NSCLC) continue to gain more treatment options, clinicians must stay abreast of updated data to facilitate detailed conversations with their patients about their treatment goals in order to select the best available therapy, according to Edward B. Garon, MD, MS.

During the 2024 ASCO Annual Meeting, investigators presented findings from the phase 3 LAURA trial (NCT03521154), which examined osimertinib (Tagrisso) following definitive chemoradiotherapy in patients with locally advanced, unresectable, stage III NSCLC. Patients who received osimertinib (n = 143) achieved a median progression-free survival (PFS) of 39.1 months (95% CI, 31.5-not calculable) vs 5.6 months (95% CI, 3.7-7.4) among patients who received placebo (n = 73; HR, 0.16; 95% CI, 0.10-0.24; P < .001). 

“Lung cancer has been considered an area where the therapies are somewhat marginal and maybe not impacting sort of meaningful benefit for the patient,” Garon said in an interview with OncLive®. “There’s been a major change within the subdivision of patients based on driver mutations based on advances in targeted therapies and immunotherapies. I would encourage practitioners to be hopeful in patients with NSCLC. This is still a very difficult disease, but many of the treatments that we have now can lead to substantial benefits for patients.”

In the OncLive, Garon a professor of medicine at UCLA Health in Los Angeles, California, discussed recent updates in NSCLC concerning antibody-drug conjugates (ADCs), targeted therapies, and perioperative treatment approaches which were shared during a recent OncLive State of the Science Summit™ on lung cancer, which he chaired.

OncLive: What is the current standing of ADCs in NSCLC and what are you keeping an eye on in the future?

Garon: There’s only 1 ADC that’s currently approved, fam-trastuzumab deruxtecan-nxki [Enhertu] in HER2-mutated NSCLC. The approval is for previously treated patients.

The real question is where we will be using that in the future, and that will really depend on regulatory approvals. There are near-term approvals that we are anticipating for patritumab deruxtecan and there also are positive phase 3 trial data at this point for datopotamab deruxtecan for even a broader patient population, with patritumab deruxtecan being for patients with EGFR mutations. The phase 3 trial of datopotamab deruxtecan, a TROP2 inhibitor, [was conducted in] a much broader population of patients.

In light of the updated data from the phase 3 CROWN trial (NCT03052608), do you see alectinib (Alecensa) retaining its role in frontline ALK+ NSCLC?

One of the things that became an interesting discussion point at the State of the Science Summit was that traditionally we have felt that the patient’s experience is going to be driven most significantly by their lung cancer. We’re now entering an era where we’re having a lot of relative decisions, where we’re having to decide how aggressive we want to be in terms of toxicity [vs] benefits. Sometimes [there are] benefits in PFS without clear data on overall survival. Many of the decisions are going to be based on the discussion between the practitioner and the patient.

Alectinib was a well-tolerated medicine. However, in cross-trial comparisons, the PFS is not as long compared with crizotinib [Xalkori] as what is seen with lorlatinib [Lorbrena]. That said, the toxicity burden of lorlatinib is greater. This will be a discussion amongst patients, the discussion between lorlatinib and alectinib. Also, [there is a] discussion between osimertinib and other approaches such as the combination of amivantamab-vmjw [Rybrevant] plus lazertinib [Leclaza].

What will be the impact of the findings from the LAURA trial that were presented during ASCO?

Probably the most significant issue about the LAURA trial is that it makes us think about locally advanced disease in EGFR mutant patients differently. The trial design was to utilize osimertinib forever. That seemed aggressive at the start of the trial.

But when we looked at the data in the control arm, nearly all patients had recurrent disease. In many respects, this is showing us that in patients with EGFR-mutated NSCLC that patients with locally advanced disease probably do need systemic therapy throughout. The data from that study was quite profound, and I believe that [approach] will become clearly the established standard at this point.

What considerations do you think about when deciding on perioperative treatment strategies?

In the very fast-moving field of lung cancer, you tend to see a lot of studies all at once compared with the same standard. That often makes it difficult to interpret data. Clearly, the data are now showing that incorporating immunotherapy into the perioperative space is beneficial.

The main challenge is figuring out how much chemoimmunotherapy to give and whether adjuvant immunotherapy is necessary in patients who would have received chemoimmunotherapy prior to surgery. If one looks at cross-trial comparisons, you can at least make the argument that continuing with adjuvant [therapy], even in patients who receive neoadjuvant therapy is beneficial. Of course, the real way to elucidate this would be in a randomized trial, and we just don’t have those data to date.

There is still a bit of a disconnect between the utilization of neoadjuvant chemoimmunotherapy in academic centers vs community practice settings. At academic centers, there has been a strong push, particularly in patients who will be needing some sort of adjuvant therapy because they have lymph node–positive disease, to incorporate chemoimmunotherapy prior to surgery. There are some theoretical reasons to think that would be better than adjuvant therapy, and the data are quite strong. One of the things that would be great [to know] coming out of [the State of the Science Summit] is whether participants saw the enthusiasm for neoadjuvant chemoimmunotherapy, particularly in patients who you know will be requiring some sort of systemic therapy.

Were there any other data updates shared during ASCO 2024 that you found notable?

The other large lung cancer study that didn’t get addressed [during the State of the Science Summit] was in small cell lung cancer [SCLC]. The [phase 3] ADRIATIC study [NCT03703297] showed that what has been the last remaining spot in lung cancer where we have not utilized immunotherapy in our upfront treatment now also has a benefit from incorporating immunotherapy. That is in patients with limited-stage SCLC, where it was definitively shown that outcomes are better if one gives durvalumab [Imfinzi] after chemoradiotherapy for limited-stage disease, as opposed to the current standard which is observation.

Reference

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