Newer Agents Hope to Raise the Bar in ALK- and RET-Positive NSCLC

Median progression-free survival (PFS) with first-line lorlatinib (Lorbrena) still has not been reached after 7 years of follow-up in the phase 3 CROWN study, with 55% of patients remaining progression-free at 84 months, a milestone for ALK-positive non–small cell lung cancer (NSCLC) reported at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting that sets a tall benchmark for the agents that followed it on the podium.¹

Three more presentations filled out the thoracic oncology session: the first phase 1/2 analysis of the ALK-selective, brain-penetrant inhibitor neladalkib in heavily pretreated patients from the ALKOVE-1 study;² the first phase 3 results for the RET inhibitor pralsetinib (Gavreto) in the first-line setting from AcceleRET-Lung;³ and pivotal phase 2 data for the next-generation, highly selective RET inhibitor lunbotinib (A400/EP0031).⁴ Discussant Angel Qin, MD, of the University of Michigan, distilled each into a single question: have these new agents "raised the bar" on survival, tolerability, or access?

"After a 7-year follow-up of the CROWN study, we have not reached the median progression-free survival, and importantly, 79% of patients who are progression-free at 2 years will remain progression-free at 7 years," said Tony S.K. Mok, MD, FRCPC, FASCO, of the Chinese University of Hong Kong, who presented the CROWN update. "This is a very important piece of information for our patients."

How far has lorlatinib pushed the survival bar?

Qin opened her ALK analysis by tracing a decade of progress: in the 2014 phase 3 PROFILE 1014 study, first-line crizotinib (Xalkori) extended median PFS to 10.9 months versus 7.0 months with chemotherapy.⁵ Ten years later, at the 5-year analysis of CROWN, median PFS with lorlatinib had not been reached.⁶ At a data cutoff of October 31, 2025, median PFS by investigator assessment remained not reached (NR) with lorlatinib (95% CI, 64.3-NR) compared with 9.1 months (95% CI, 7.4-10.9) with crizotinib in the 296-patient CROWN trial (hazard ratio [HR], 0.19; 95% CI, 0.13-0.27).¹ Only 7 new PFS events occurred between years 5 and 7. Intracranial activity continued to deepen: 92% of lorlatinib-treated patients remained free of CNS progression at 84 months, with no new intracranial events after the first 30 months.

Overall survival (OS) data remained immature, with 123 of 296 patients dead at cutoff, which was below the 139 deaths required for the protocol-specified second OS interim analysis. "It's not that it's not available. We are not supposed to look at it yet," Mok said in the panel discussion that followed.

Can lorlatinib solve its tolerability and access problem?

If lorlatinib raised the survival bar, "tolerability remains a challenge," Qin said. Any-grade adverse events (AEs) at the 15%-or-higher incidence threshold included hypercholesterolemia (73%), hypertriglyceridemia (71%), edema (58%), peripheral neuropathy (46%), weight gain (45%), and cognitive effects (30%). Dose reductions occurred in 34% of patients (median time to first reduction, 25 weeks).¹ Mok emphasized that efficacy was preserved across the 100-mg, 75-mg, and 50-mg dose levels. "Dose modification is key," Qin said and, in the panel, Mok said he does not mind starting at a lower dose for elderly patients.

Access is the third constraint. Lorlatinib is approved in 60 countries but is not routinely accessible in many low- and middle-income countries, Qin noted, which is an open question the CROWN data alone cannot answer.

Does neladalkib have a role after lorlatinib?

Jessica J. Lin, MD, of the Mass General Brigham Cancer Institute, presented the first phase 1/2 analysis of neladalkib, an ALK-selective, brain-penetrant, TRK-sparing TKI, from the ALKOVE-1 study (NCT05384626).² Among 253 ALK TKI-pretreated patients with measurable disease by blinded independent central review (BICR), 75% had received prior lorlatinib and the median number of prior anticancer regimens was 3 (range, 1-11). The objective response rate (ORR) by BICR was 31% overall (95% CI, 26%-37%), 46% in lorlatinib-naive patients (95% CI, 33%-59%), and 26% in lorlatinib-experienced patients (95% CI, 20%-33%). Median PFS was 14.5 months in lorlatinib-naive patients but 4.6 months in lorlatinib-experienced patients, which was "modest," in Qin's framing.

Neladalkib distinguished itself in resistant tumors. In the G1202R subgroup (n = 47), ORR was 68% overall and 83% in lorlatinib-naive patients (n = 12), with an 18-month duration of response (DOR) rate of 77%. In patients with more than 2 ALK mutations who had received at least 2 prior ALK TKIs (n = 43), ORR was 58%. A preliminary 44-patient TKI-naive cohort showed an 86% confirmed ORR (complete response rate, 9%; 12-month DOR rate, 91%), supporting the ongoing phase 3 ALKAZAR trial (NCT06765109), Lin said.

Qin's side-by-side AE comparison at the 15% threshold highlighted the trade-off, although cross trial comparisons are often discouraged. Neladalkib produced higher rates of any-grade transaminase elevation (ALT, 47% vs 19% with lorlatinib; AST, 44% vs 16%) and dysgeusia (23% vs 6%), while lorlatinib's hypercholesterolemia, hypertriglyceridemia, peripheral neuropathy, weight gain, edema, and cognitive effects were largely absent at the 15% threshold with neladalkib.² Treatment-related dose reductions occurred in 17% of the 656-patient neladalkib safety population, and 5% discontinued because of treatment-emergent AEs.

The phase 3 ALKAZAR trial randomizes neladalkib against alectinib (Alecensa) in the first-line setting. The study was “in alignment with the FDA at the time the study was designed, when alectinib was widely used as the comparator," Lin said in the panel. "Certainly, the efficacy data that we see from the ALKOVE-1 [trial] in terms of activity after lorlatinib, as well as its differentiated safety profile, would justify the exploration of neladalkib after lorlatinib,” she added. Asked whether second-generation ALK TKIs retain a role after lorlatinib failure, Mok said crizotinib is not his choice "because of its CNS profile," but acknowledged "the debate is on the second-generation product."

Does AcceleRET-Lung cement pralsetinib as a first-line standard?

Sanjay Popat, PhD, FRCP, of the Royal Marsden Hospital & Institute of Cancer Research, presented results from the phase 3 AcceleRET-Lung study (NCT04222972), the first randomized trial of a selective RET inhibitor against platinum-based standard-of-care (SOC) chemotherapy with or without pembrolizumab (Keytruda) in the first-line treatment of advanced RET fusion-positive NSCLC.³

Among 223 treatment-naive patients randomly assigned 1:1 to pralsetinib (n = 110) or investigator's choice of platinum-based SOC (n = 113), median PFS by investigator assessment was 18.7 months (95% CI, 11.1-25.2) with pralsetinib versus 9.0 months (95% CI, 7.1-11.5) with SOC, which was a 41% reduction in the risk of progression or death (HR, 0.59; 95% CI, 0.42-0.84; P = .0027). ORR was 65.5% versus 41.6% (P = .0002), and median DOR was 20.6 versus 9.7 months.

Median OS was not reached with pralsetinib versus 39.8 months with SOC (HR, 1.09; 95% CI, 0.65-1.85; P = .742); the analysis was immature, with at least 70% of patients alive in each arm, and 38 SOC patients had crossed over to pralsetinib. The trial was terminated by the original sponsor on January 27, 2025, at 98.7% of target accrual.

"These results substantiate the use of pralsetinib as a first-line standard-of-care option in advanced RET fusion-positive NSCLC consistent with current guidelines," Popat said. Qin called the results "practice confirming," contextualizing them against the phase 3 LIBRETTO-431 study of selpercatinib (Retevmo), in which median PFS was 24.8 months versus 11.2 months with chemotherapy with or without pembrolizumab (HR, 0.46; 95% CI, 0.31-0.70; P <.001).⁷

What's driving pralsetinib's infection signal?

Tolerability was the central question in Qin's analysis of pralsetinib. Grade ≥3 infections occurred in 28.7% of patients on pralsetinib versus 9.6% on SOC, and 8 fatal infection events (7.4%) occurred in the pralsetinib arm compared with 0 on SOC.³ After an urgent protocol amendment in October 2024 communicated the risk and provided monitoring and dose-modification guidance, 28 patients remained on pralsetinib without further infection-related deaths.

Asked about the mechanism in the panel, Popat said the link between cytopenias and the fatal infections was not clear-cut: when investigators analyzed the fatal events, "the vast majority of these were not associated with lymphopenia or neutropenia prior to the event." Only one event was associated with febrile neutropenia, he said. Informing investigators of the risk and mitigating with early dose reductions has reduced the signal in practice.

Where does lunbotinib fit?

Qing Zhou, MD, PhD, of the Guangdong Lung Cancer Institute, reported pivotal phase 2 results (NCT05265091) of lunbotinib (A400/EP0031), a next-generation selective RET inhibitor with 93-fold greater selectivity for RET than for VEGFR2.⁴

The China-only trial enrolled 91 treatment-naive and 70 pretreated patients who received lunbotinib 90 mg once daily. Confirmed ORR by independent review committee was 81.3% in treatment-naive patients and 87.1% in pretreated patients. Median PFS was not reached in treatment-naive patients (24-month PFS rate, 59.9%) and was 27.5 months in pretreated patients (52.1% at 24 months). Intracranial ORR by RANO-BM among 16 patients with measurable baseline brain lesions was 62.5%. Grade ≥3 treatment-related AEs occurred in 40.5% of the 163-patient safety population, with a 1.2% treatment-related discontinuation rate and no treatment-related deaths.

"Lunbotinib monotherapy demonstrated robust and durable antitumor activity in RET fusion-positive non–small cell lung cancer in both treatment-naive and pretreated patients, with manageable toxicity," Zhou said. Asked about the lowest effective dose in the panel, she said 50 mg once daily was the lowest dose tested, and at that level "patients do not have too much of toxicity."

In Qin's reading, the response rates are impressive but the data leave open questions: lunbotinib has not been tested after pralsetinib or selpercatinib, the pretreated cohort had no prior selective RET TKI exposure, and the trial was conducted entirely in China in patients with ECOG performance status 0 or 1. On-target resistance mutations such as G810S/C/R and off-target resistance pathways are unaddressed by the available data.

Has the bar been raised?

In her summary, Qin concluded that lorlatinib's durability "confirms how it should be used as front-line treatment for metastatic ALK-positive non–small cell lung cancer," but "this drug has very limited global availability." Neladalkib offers an emergent option for relapsed/refractory disease, "but we do need data regarding activity post currently approved [next-generation] TKIs." AcceleRET-Lung is "practice confirming" for first-line pralsetinib. And lunbotinib is "a novel RET TKI that we need some more data on."

References

1. Mok TS, Solomon BJ, Felip E, et al. Lorlatinib vs crizotinib as first-line treatment for advanced ALK+ non-small cell lung cancer: 7-year update from the phase 3 CROWN study. J Clin Oncol. 2026;44(suppl 16):8502. doi:10.1200/JCO.2026.44.16_suppl.8502

2. Lin JJ, Felip E, Cho BC, et al. ALKOVE-1: efficacy and safety of neladalkib in patients with advanced ALK+ NSCLC. J Clin Oncol. 2026;44(suppl 16):8503. doi:10.1200/JCO.2026.44.16_suppl.8503

3. Popat S, Besse B, Calles A, et al. Efficacy and safety of pralsetinib as first-line treatment of RET fusion-positive advanced or metastatic non-small cell lung cancer: the phase 3 AcceleRET-Lung study. J Clin Oncol. 2026;44(suppl 16):8504. doi:10.1200/JCO.2026.44.16_suppl.8504

4. Zhou Q, Wu YL, Li X, et al. Efficacy and safety of lunbotinib (A400/EP0031), a next-generation selective RET inhibitor (SRI), from a pivotal phase II study in patients with advanced RET-fusion positive non-small cell lung cancer (NSCLC). J Clin Oncol. 2026;44(suppl 16):8505. doi:10.1200/JCO.2026.44.16_suppl.8505

5. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167-2177. doi:10.1056/NEJMoa1408440

6. Solomon BJ, Liu G, Felip E, et al. Lorlatinib versus crizotinib in patients with advanced ALK-positive non–small cell lung cancer: 5-year outcomes from the phase III CROWN study. J Clin Oncol. 2024;42(29):3400-3409. doi:10.1200/JCO.24.00581

7. Zhou C, Solomon B, Loong HH, et al. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion-positive NSCLC. N Engl J Med. 2023;389(20):1839-1850. doi:10.1056/NEJMoa2309457