Key Data Updates From ASCO May Advance the Treatment Landscapes of 3 Lung Cancer Subtypes

Suresh S. Ramalingam, MD, FACP, FASCO

As the lung cancer treatment paradigm continues to evolve and advance, investigators continue to develop increasingly effective therapies for patients in specific, and in some cases previously underserved, disease subtypes. Although the disease remains the leading cause of cancer-related death worldwide, there is great hope among experts in the field that outcomes for patients with lung cancer will only continue to improve in the coming years.¹

“It’s a very exciting time for patients with lung cancer because of the availability of targeted and immunotherapy treatment options,” Suresh S. Ramalingam, MD, FACP, FASCO, executive director of Winship Cancer Institute of Emory University and associate vice president for cancer at Woodruff Health Sciences Center in Atlanta, Georgia, said in an interview with OncologyLive. “We’re seeing improvements in patients with small cell lung cancer [SCLC] and with non–small cell lung cancer [NSCLC]. Overall, patients with lung cancer are living better and living longer, and that is thanks to the amazing therapeutic advances that have been made in the past few years.”

NSCLC is the most common type of lung cancer, representing approximately 85% of cases. Despite the overall poor prognosis the disease carries—the 5-year overall survival (OS) rate is approximately 17%—a variety of targeted approaches and immunotherapeutics have gained traction in the space and improved upon outcomes seen with traditional surgery, chemotherapy, and/or radiotherapy.¹ Since 2020, 16 agents have been approved by the FDA in various disease settings of NSCLC.²

On the other hand, patients with SCLC have not experienced as many robust advances in recent years. SCLC remains a highly aggressive subtype that represents approximately 15% of all lung cancer diagnoses; although it is often initially responsive to chemotherapy, most patients relapse, and the 5-year OS rate is less than 7%.³

Specifically, patients with limited-stage SCLC (LS-SCLC) have not seen a major treatment advance beyond the standard of care for decades. The current standard treatment, concurrent chemoradiotherapy, confers a median OS that ranges between 25 and 30 months.⁴

During the plenary session at the 2024 American Society of Clinical Oncology Annual Meeting (ASCO 2024), in June in Chicago, Illinois, investigators presented findings from 3 phase 3 clinical studies with the potential to rewrite the standard of care in patients with oncogene-driven NSCLC and LS-SCLC.

LAURA and CROWN Shake Up the EGFR and ALK Spheres

The phase 3 LAURA trial (NCT03521154) was a double-blind, placebo-controlled study that enrolled adult patients with locally advanced, unresectable, stage III NSCLC with an EGFR exon 19 deletion or L858R mutation whose disease did not progress following definitive chemoradiotherapy. Eligible patients were randomly assigned 2:1 to receive oral osimertinib (Tagrisso) 80 mg or placebo once daily. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR) per RECIST v1.1; secondary end points included overall survival (OS), central nervous system PFS, and safety.⁵

“Presently in this group of patients, concurrent chemoradiation followed by immunotherapy has been the standard of care. But that is not something that works well for patients with an EGFR mutation, [and] that is why we conducted this study,” Ramalingam, who was the lead study author, explained.

Findings from the primary analysis of LAURA presented during ASCO 2024 by Ramalingam demonstrated that the median PFS per BICR in the osimertinib arm (n = 143) was 39.1 months (95% CI, 31.5-not calculable [NC]) vs 5.6 months (95% CI, 3.7-7.4) in the placebo arm (n = 73). Treatment with osimertinib conferred an 84% reduction in the risk of progression or death compared with placebo (HR, 0.16; 95% CI, 0.10-0.24; P < .001). The 12- and 24-month PFS rates were 74% and 65%, respectively, in the investigational arm vs 22% and 13%, respectively, in the control arm.

The objective response rates (ORR) by BICR in the osimertinib and placebo arms were 57% (95% CI, 49%-66%) vs 33% (95% CI, 22%-45%), respectively. The median duration of response (DOR) was 36.9 months (95% CI, 30.1-NC) vs 6.5 months (95% CI, 3.6-8.3), respectively. OS data were 20% mature at the time of the presentation, but favored the osimertinib arm (HR, 0.81; 95% CI, 0.42-1.56; P = .530).

“We found that the [PFS] benefit was seen across all key subgroups of patients enrolled to the study,” Ramalingam added. “It is widely applicable to this patient population regardless of age, gender, or the specific type of mutation. We [also] saw that the safety profile was consistent with what we would expect with osimertinib alone.”

Osimertinib was well tolerated over the course of LAURA; most adverse effects (AEs) in the investigational arm were low grade with 1 patient experiencing an AE leading to death that was deemed possibly related to treatment. Patients in the osimertinib and placebo arms experienced grade 3 or higher AEs (35% vs 12%), AEs leading to death (2% vs 3%), and serious AEs (38% vs 15%). The most common any-grade AEs reported in at least 10% of patients in the osimertinib arm included radiation pneumonitis (48%), diarrhea (36%), and rash (24%).

“This will have an immediate impact on management of patients with stage III locally advanced EGFR-mutated [NSCLC],” Ramalingam said. “Right now, we [prescribe] chemotherapy and radiation and then we just follow [patients]. The LAURA study showed that if patients do not get any further therapy, within 5 to 6 months, half of the patients have disease progression. Using osimertinib in this setting, a drug that is approved and available for stage IV disease and earlier resected lung cancer, would be an easy integration into standard treatment algorithms. We believe this trial will change the standard of care for this subset of patients.”

In ALK-positive NSCLC, findings presented during ASCO 2024 from the phase 3 CROWN trial (NCT03052608) displayed the longest PFS ever reported in advanced NSCLC. CROWN enrolled patients with stage IIIB/IV ALK-positive NSCLC who did not receive prior systemic therapy for metastatic disease and randomly assigned them 1:1 to receive lorlatinib (Lorbrena) 100 mg once daily or crizotinib (Xalkori) 250 mg twice daily. The primary end point was PFS by BICR; secondary end points included ORR, OS, and safety (Figure).⁶

Figure. Progression-Free Survival in the Phase 3 CROWN Study

At a median PFS follow-up of 60.2 months (95% CI, 57.4-61.6) in the lorlatinib arm (n = 149) vs 55.1 months (95% CI, 36.8-62.5) in the crizotinib arm (n = 147), the median PFS was not reached (NR; 95% CI, 64.3-NR) compared with 9.1 months (95% CI, 7.4-10.9), respectively (HR, 0.19; 95% CI, 0.13-0.27). The 5-year PFS rates were 60% vs 8%, respectively.

Notably, lorlatinib provided a significant PFS benefit vs crizotinib both in patients with (HR, 0.08; 95% CI, 0.04-0.19) and without (HR, 0.24; 95% CI, 0.16-0.36) brain metastases. Additionally, lorlatinib significantly extended time to intracranial progression compared with crizotinib (HR, 0.06; 95% CI, 0.03-0.12).

“[The CROWN data] were outstanding; maybe some of the best targeted data we have seen in lung cancer,” David R. Spigel, MD, medical oncologist and chief scientific officer at Sarah Cannon Research Institute, in Nashville, Tennessee, said in an interview with OncologyLive. “I would argue it is some of the best data ever seen in oncology, in terms of patients living for 5 years without their cancer returning. That really is quite amazing.”

ADRIATIC Reshapes Thinking in SCLC

During ASCO 2024, Spigel presented findings from the phase 3 ADRIATIC study (NCT03703297), which examined the PD-L1– directed antibody durvalumab (Imfinzi) as consolidation therapy following concurrent chemoradiation in patients with stage I to III LS-SCLC who did not experience disease progression after chemoradiation. Patients were randomly assigned to receive durvalumab 1500 mg every 4 weeks, placebo every 4 weeks, or durvalumab 1500 every 4 weeks plus tremelimumab (Imjudo) 75 mg every 4 weeks for 4 doses followed by durvalumab monotherapy. The co–primary end points were OS and PFS by BICR per RECIST v1.1 for durvalumab vs placebo.⁴

“[Chemoradiation] has been the standard of care for decades, but most patients have their cancer come back within 2 years, and [approximately] less than a third of patients will make it beyond 5 years,” Spigel noted. “Our current standard of treatment is just not good enough to help patients when your goal is to cure them. ADRIATIC was designed to see if using immunotherapy after chemotherapy and radiation can improve [outcomes].”

During the presentation, Spigel shared results from the durvalumab monotherapy and placebo arms, noting that data from the combination arm will be shared at a later date. At a median follow-up of 37.2 months (range, 0.1-60.9) patients treated with durvalumab (n = 264) achieved a median OS of 55.9 months (95% CI, 37.3-not evaluable) vs 33.4 months (95% CI, 25.5-39.9) among patients who received placebo (n = 266), leading to a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.57-0.93; P = .0104). At a median follow-up of 27.6 months (range, 0.0-55.8), the median PFS was 16.6 months (95% CI, 10.2-28.2) vs 9.2 months (95% CI, 7.4-12.9), respectively (HR, 0.76; 95% CI, 0.61-0.95; P = .0161).

The 24- and 36-month OS rates were 68.0% and 56.5%, respectively, in the durvalumab arm; these rates were 58.5% and 47.6% in the placebo arm. The 24- and 36-month PFS rates were 48.8% and 46.2% respectively, in the durvalumab arm; these rates were 36.1% and 34.2% in the placebo arm.

Findings from a subgroup analysis showed that the OS benefit of durvalumab over placebo was observed regardless of patient characteristics. The most pronounced benefit with durvalumab was reported in patients who were randomly assigned to the drug less than 14 days after concurrent chemoradiation (HR, 0.47; 95% CI, 0.24-0.91), those who achieved stable disease following concurrent chemoradiation (HR, 0.54; 95% CI, 0.25-1.13), and those with a World Health Organization performance status of 0 (HR, 0.55; 95% CI, 0.38-0.79).

“The study met both of its primary end points,” Spigel commented. “This is a new standard of care, and durvalumab will hopefully have its label expanded where it is already available. This will be something doctors, patients, and families will want to get access to as soon as possible. I believe this will change care for us starting today, and that is good news for our patients.”

Durvalumab also displayed a tolerable safety profile in LS-SCLC; patients discontinued treatment due to AEs at a rate of 16.4% vs 10.6% in the monotherapy and placebo arms, respectively, and death due to AEs was reported at respective rates of 2.7% vs 1.9%. Patients in both arms experienced serious AEs (29.8% vs 24.2%), any-grade immune-mediated AEs (32.1% vs 10.2%), and grade 3 or 4 immune-mediated AEs (5.3% vs 1.5%). The most common any-grade AEs in the durvalumab arm included radiation pneumonitis (22.9%), decreased appetite (16.8%), and hypothyroidism (16.0%).

“There is this wave of other drugs coming, [including] antibody-drug conjugates, bispecifics, and other immunotherapy combinations,” Spigel said in conclusion. “These are naturally going to be things we want to study in earlier treatment settings like first-line extensive-stage SCLC and LS-SCLC. This is kind of a stair-step approach. Now that durvalumab has shown benefit and we have other drugs showing benefit, can you combine them? Do you use them in sequence? These will be the next big questions.”

References

1. Araghi M, Mannani R, Heidarnejad Maleki A, et al. Recent advances in non-small cell lung cancer targeted therapy; an update review. Cancer Cell Int. 2023;23(1):162. doi:10.1186/ s12935-023-02990-y
2. FDA approvals in lung cancer treatment. Lung Cancer Research Foundation. Accessed June 6, 2024. https://www.lungcancerresearchfoundation.org/research/why-research/treatment-advances/
3. Patel SR, Das M. Small cell lung cancer: emerging targets and strategies for precision therapy. Cancers (Basel). 2023;15(16):4016. doi:10.3390/cancers15164016
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
5. 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
6. 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.2024.42.17_suppl.LBA8503