Wakelee Addresses NSCLC Treatment Considerations From Every Angle

Heather Wakelee, MD

Giving a glimpse into significant data and highlighting the importance of balancing toxicities with efficacy as the non–small cell lung cancer (NSCLC) treatment paradigm shifts, Heather Wakelee, MD, explained that the abun- dance of data presented over the course of 2023 in the NSCLC realm has made for more complex decision-making. In an interview with OncologyLive®, Wakelee detailed debates that have arisen among clinicians due to recent advances.

She notes these include how to best sequence osimertinib (Tagrisso) for patients with EGFR mutations, and data from the phase 3 MARIPOSA-2 trial (NCT04988295) raise the ques- tion about which patients will benefit most from treatment with amivantamab-vmjw (Rybrevant) plus chemotherapy.

During the 2nd Annual Hawaii Lung: A Multidisciplinary Case-Based ConferenceTM, which is slated to occur on January 20, 2024, medical oncologists, radiation oncologists, and surgeons will gather to confer on these topics in addi- tion to others, discussing how these advances in lung cancer treatment can be applied to practice as well.

“What are the systemic treatments that one would think about in early- stage [treatment], which has been rapidly changing with the 8 recent trials that are coming out? [At Hawaii Lung,] we’ll talk about the neoadjuvant data, adjuvant data, and the 5 perioperative trials that have come out in 2023; what would make sense for [a given] patient; and what the different aspects are in making those decisions,” she explained in the interview. Wakelee is a professor of medi- cine and chief of the Division of Oncology at Stanford University School of Medicine, deputy director and division chief of Medical Oncology at Stanford Cancer Institute, in Palo Alto, California, and president of the International Association for the Study of Lung Cancer.

Evolving Data Continue to Shift the EGFR-Mutated Landscape

“There was some excitement in the EGFR- [mutated] space, where we had the phase 3 PAPILLON trial [NCT04538664] of chemother- apy plus or minus amivantamab for patients with EGFR exon 20–[mutated disease]. That showed a significant improvement in progression-free survival [PFS]—yes, with toxicity—but the PFS HR was 0.40, which was quite striking, and so that becomes a new standard,” Wakelee said.

Patients with advanced NSCLC and EGFR exon 20 insertions who had not received previ- ous systemic therapy enrolled in the PAPILLON trial achieved a median PFS of 11.4 months (95% CI, 9.8-13.7) in the amivantamab/chemo- therapy arm (n = 153) vs 6.7 months (95% CI, 5.6-7.3) in the chemotherapy-alone arm (n = 155; HR, 0.40; 95% CI, 0.30-0.53; P < .001). The median overall survival (OS) was not estimable (NE; 95% CI, NE-NE) in the combination arm vs 24.4 months (95% CI, 22.1-NE) in the chemother- apy arm (HR, 0.67; 95% CI, 0.42-1.09; P = .11). The 24-month OS rates were 72% (95% CI, 61%-81%) vs 54% (95% CI, 37%-68%), respectively.¹

Regarding safety, serious adverse effects (AEs) occurred in 37% of patients in the amivantamab/ chemotherapy arm and 31% of patients in the chemotherapy arm. Dose interruptions (69% vs 36%, respectively), reductions (48% vs 23%), and discontinuations (24% vs 10%) occurred due to AEs. The most common grade 3 or higher AEs experienced by patients in the amivantamab/chemotherapy arm were neutropenia (33%), leukopenia (11%), and rash (11%), and the most common expe- rienced in the chemotherapy arm were neutropenia (23%), anemia (12%), and thrombocytopenia (10%).¹

“When we look at the MARIPOSA-2 data, chemotherapy [plus] amivantamab was quite promising, but with toxicity that we need to work on how to best manage, and [there are] a lot of questions around the patients who are benefiting are,” Wakelee noted. “How we look at those biomarkers further [is a key question].”

Primary results from the MARIPOSA-2 trial revealed that patients with EGFR-mutated locally advanced or metastatic NSCLC who experienced disease progression on osimertinib achieved a significant improvement in PFS when given amivantamab with or without lazertinib (Leclaza) plus chemotherapy vs chemotherapy alone. Patients who received triplet therapy with amivan- tamab, lazertinib, and chemotherapy (n = 263) achieved a median PFS of 8.3 months (95% CI, 6.8-9.1) vs 6.3 months (95% CI, 5.6-8.4) for those who received amivantamab plus chemotherapy (n = 131) vs 4.2 months (95% CI, 4.0-4.4) for those who received chemotherapy alone (n = 263). The HR was 0.48 (95% CI, 0.36-0.64; P < .001) for the doublet vs chemotherapy and 0.44 (95% CI, 0.35- 0.56; P < .001) for the triplet vs chemotherapy.²

Grade 3 or higher AEs occurred in 72% of patients treated with the doublet, 92% given the triplet, and 48% of patients given chemother- apy alone. Serious treatment-emergent AEs were reported in 32.0%, 52.0%, and 20.0% of patients, respectively, and treatment-related AEs led to death in 2.0%, 2.0%, and 0.4% of patients.²

“[We are] continuing the debate around, is osimertinib [the] first-line [treatment] for patients with classic EGFR mutations?...For the most part, people will still be thinking about osimertinib by itself and then bringing agents [such as lazertinib or amivantamab] in later,” Wakelee said.

She also noted that “more work is needed to try to understand which patients are benefiting” as well as “if you combine [agents], you’re going to have a longer PFS, but is throwing everything together better than doing it sequentially? We haven’t answered that question [on] the concur- rent vs sequential [treatment decision] or how that’s going to impact OS.”

Recent Statistically Significant Data Shed Light on Optimal Approaches

Data from the phase 3 TROPION-LUNG01 study (NCT04656652) revealed that patients with advanced or metastatic NSCLC treated with dato- potamab deruxtecan (Dato-DXd; DS-1062a) experienced a statistically significant improve- ment in PFS compared with patients given docetaxel monotherapy.³

“When we talk about metastatic disease for all comers, [the] trial of Dato-DXd vs docetaxel in the second line was the first randomized phase 3 study to show a PFS survival benefit [with an agent] vs standard docetaxel. But it was at a cost of an increase in toxicity and [came] without a clear biomarker that helps us pick which patients are more likely to benefit, other than histology—where the squamous [population] didn’t [experience a benefit]. That was an important update.”

Findings presented at the 2023 European Society for Medical Oncology (ESMO) Congress in the subgroup of patients with nonsquamous histology showed that the median PFS for those who received Dato-DXd (n = 229) was 5.6 months (95% CI, 4.4-7.0) compared with 3.7 months (95% CI, 2.9-4.2) in the docetaxel arm (n = 232; HR, 0.63; 95% CI, 0.51-0.78). Patients with nonsquamous histology were among those who received the most benefit from treatment with Dato-DXd vs docetaxel; those with actionable genomic alterations (HR, 0.38), brain metastases at baseline (HR, 0.64), and those in the intention- to-treat population (HR, 0.75) also experienced a significant PFS benefit with the TROP-2–directed antibody-drug conjugate.³

Comparatively, the median PFS was 2.8 months (95% CI, 1.9-4.0) in the Dato-DXd arm (n = 70) vs 3.9 months (95% CI, 2.8-4.5) in the docetaxel arm (n = 73) among patients with squamous histology (HR, 1.38; 95% CI, 0.94-2.02).

Investigators Hope to Discuss Lingering Questions in Metastatic Disease

Although the standard treatment for locally advanced NSCLC remains chemotherapy/ radiation followed by durvalumab (Imfinzi), according to Wakelee, therapies for metastatic disease are shifting.

We still know in the first line for patients who do not have a driver mutation in their tumor that we have a lot of different choices, [including] a checkpoint inhibitor, checkpoint inhibitor plus chemotherapy, [and] dual checkpoint inhibitors,” Wakelee explained. “[We are] trying to figure out what’s the best for any given patient, so there is a lot of discussion and debate around that.”

In the perioperative space, in October 2023, the FDA approved pembrolizumab (Keytruda) plus platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of pembrolizumab monotherapy as postsurgical adjuvant treatment for patients with resectable NSCLC.⁴ Data from the phase 3 KEYNOTE-671 trial (NCT03425643) demonstrated that the median OS was not reached (NR; 95% CI, NR-NR) in the pembrolizumab-plus-chemotherapy arm (n = 397) vs 52.4 months (95% CI, 45.7-NR) in the arm receiving placebo plus platinum-based chemotherapy (n = 400; HR, 0.72; 95% CI, 0.56- 0.93; P = .0103).⁵

“KEYNOTE-671 has led to the approval of pembrolizumab in the neoadjuvant and adju- vant perioperative settings with an OS benefit that’s been proven. It’s likely that some of the other trials will lead to approvals as well as they hit their OS end points,” Wakelee said. “Any patient who does not have a driver mutation or a contraindication with stage III and many with stage II [disease] at this time are all treated with chemotherapy plus immunotherapy in the neoadjuvant setting. What’s the additional benefit of perioperative vs the pure neoadjuvant with
a CheckMate 816 [NCT02998528] regimen [of neoadjuvant nivolumab (Opdivo) plus chemother- apy]? That’s one of the areas that we continue
to debate as to which patients benefit from the extension [of treatment] and which patients might not. We still have other work to do to answer those questions.”

Follow-Up Data and Circulating Tumor DNA

Delving into the role of circulating tumor DNA (ctDNA), Wakelee explained that liquid biopsies are evolving. “We don’t have any that are commercially available that are [sensitive] enough after surgery to say this patient has truly been cured, and there’s a lot of research being done in that space,” Wakelee said. “We need to take some of the newer ctDNA technology, which isn’t developed quite enough yet, to help deter- mine [whether] there are patients who were cured already with surgery and don’t need [treat- ment with] alectinib [Alecensa]. For patients who get started on alectinib, most of them are likely going to need it for a much longer period of time. I don’t think we cure people with tyrosine kinase inhibitors.”

Longer follow-up data will also aid in deci- sion-making, although early data have shown promise, according to Wakelee. Data from the phase 3 ALINA trial (NCT03456076) presented at the 2023 ESMO Congress revealed that treat- ment with the oral ALK inhibitor alectinib resulted in a significant improvement in disease- free survival vs chemotherapy for patients with ALK-positive NSCLC.⁶

“We need a lot longer follow-up on the ALINA trial to see what happens after the 2 years. But we likely have just postponed when we’re going to see those recurrences,” Wakelee said. “It’s a very significant improvement for patients [for us] to be able to say, ‘We can give you this targeted agent after your surgery because we do think that it’s going to be what prevents the cancer from recurring.’ But we’re going to need to look at that longer-term follow-up, and we need to be looking at trials to give a much longer duration.”

Findings from the ALINA trial showed that median disease-free survival among patients with stage IB to IIIA ALK-positive NSCLC was NE (95% CI, NE-NE) for those treated with alectinib (n = 130) vs 41.3 months (95% CI, 28.5-NE) for those given chemotherapy (n = 127; stratified HR, 0.24; 95% CI, 0.13-0.43; P < .0001).⁶

“It’ll be great at the Hawaii meeting to talk about what do all these [data] mean in the context of a patient who comes in to see you and how we make our decisions,” Wakelee said.