Ficonalkib: a new contender in ALK-positive non-small cell lung cancer treatment

Introduction

Seventeen years ago, the discovery of anaplastic lymphoma kinase (ALK) fusion in non-small cell lung cancer (NSCLC) revolutionized the treatment of ALK-positive NSCLC (1). About 4% of NSCLC cases, mainly affecting young never or light smokers with adenocarcinoma histology, exhibit this molecular alteration (2). Advances in treatment have translated in significant survival gain for these patients, with reported median overall survival (OS) exceeding 5 years in select cohorts (3,4).

Following the approval of crizotinib, a first-generation tyrosine kinase inhibitor (TKI), in 2011, several next-generation ALK TKIs were approved (5). These include second-generation TKIs such as ceritinib, alectinib, and brigatinib, and the third-generation TKI lorlatinib. Currently, alectinib, brigatinib, and lorlatinib are recommended as first-line treatments due to their better central nervous system (CNS) penetration and survival advantage over crizotinib (6-9).

Ultimately, all ALK-positive NSCLC patients experience progression on ALK TKIs due to resistance, which can be broadly categorized as on-target or off-target. After progression on second-generation ALK TKIs, primarily on-target resistance mutations develop in 50–60% of patients. Lorlatinib, however, has a significantly higher incidence of off-target resistance compared to on-target resistance (10). Lorlatinib can overcome most resistance mutations to first- and second-generation ALK TKIs, including G1202R, and it is a standard treatment in this setting, with a 47% overall response rate (ORR), a 63% CNS ORR, and a median progression-free survival (mPFS) of 7.3 months in second or later lines of treatment (4,10).

With one effective third-generation ALK TKI already approved, is there a need for more similar drugs? Lorlatinib is highly effective, with excellent brain penetration, but has a peculiar adverse event profile (weight gain, hyperlipidaemia, neurocognitive side effects, etc.) (9,11). Ficonalkib is a highly active, CNS-penetrant, third-generation inhibitor with high ALK selectivity, potentially improving the side effect profile. Furthermore, in vitro assays have shown that ficonalkib is active against a range of ALK mutations that emerge following treatment with first- and/or second-generation inhibitors (12). In the following paragraphs, we will review data from the first-in-human phase 1/2 trial evaluating this novel third-generation ALK inhibitor (12).

Trial design

This first-in-human, multicentre, open-label study comprised a phase 1 part involving dose escalation and dose expansion with safety as the primary endpoint, followed by a phase 2 part where the primary objective was the ORR.

The dose escalation approach chosen was the classic 3 + 3 modified Fibonacci method, a widely used but not the most efficient technique in drug development (13). The aforementioned method, developed in the chemotherapy era, primarily focuses on dose-limiting toxicities. In contrast, small molecules like ficonalkib can achieve an optimal biological dose without inducing severe toxicity. Notably, although pharmacokinetic data were collected, the study did not examine receptor occupancy or other biological effects, which might have enhanced drug development accuracy. Modern approaches like continual reassessment method (CRM) allow for a more flexible, data-driven dose-escalation strategy (13). Nevertheless, doses showing preliminary signs of efficacy and safety were expanded, and the maximum tolerated dose was not reached.

Patients were recruited from several institutions across China, which may limit the generalizability of the results to other global regions. The phase 1 included both treatment-naive (n=2) and pretreated patients, whereas the phase 2 was restricted to patients who had received at least a second-generation ALK TKI.

It is important to highlight that almost 50% of the patients in the full analysis set had received prior chemotherapy, which does not reflect the standard clinical practice since the approval of lorlatinib. Lastly, as ficonalkib, like other third-generation ALK inhibitors, has a good CNS penetration, patients with asymptomatic or neurologically stable brain metastases were included in the study.

Results

The primary focus of evaluating new drugs lies in their safety and early signs of efficacy. In the following sections, we will analyse and contextualize the toxicity profile and efficacy data emerging from this phase 1/2 trial.

Safety

The dose-escalation phase of the study included 29 patients receiving ficonalkib doses ranging from 25 to 800 mg QD. Doses of 500 and 600 mg QD were taken forward for the dose-expansion phase, during which no patient experienced dose-limiting toxicities.

Treatment-related adverse events (TRAEs) on ficonalkib occurred in 90.9% of patients treated in the phase 2 part of the study, with 14.8% of patients experiencing grade 3 or 4 toxicity. Dose reductions and discontinuations occurred in 14 (15.1%) and 1 (1.1%) patients, respectively, which compares favourably with the phase 2 lorlatinib data (22% and 3%). Importantly, there were no treatment-related deaths. The key safety and efficacy findings from the early-phase trials of ficonalkib and lorlatinib are presented in Table 1. Toxicity predominantly impacted the gastro-intestinal system, with 75% of patients experiencing diarrhoea, and 46.6% and 43.2% reporting vomiting and nausea, respectively. Despite this, the incidence of grade ≥3 toxicity remained low (14.8%) compared to 72% of patients experiencing grade ≥3 toxicity on lorlatinib in the CROWN trial (9). All the grade ≥3 toxicities resolved with discontinuation of ficonalkib. Interestingly, the neuro-cognitive side effects frequently observed on lorlatinib were not reported with ficonalkib. This, added to the lack of hypertriglyceridemia, confers a differential toxicity profile to ficonalkib. Whilst these data on TRAEs are encouraging, the incidence of treatment-emergent adverse events was not reported, which could have provided further insight into ficonalkib’s toxicity profile.

Efficacy

The study included a total of 124 patients, of which 88 patients received ficonalkib at the recommended phase 2 dose (600 mg QD), and all these patients had received prior lines of ALK-targeted treatment. Half of the phase 2 patients (n=44) had received only one prior line of second-generation ALK TKI. ORR was 40% in line with previous data on ALK-targeted drugs, the time to response for ficonalkib was short (3.6 months) with a median duration of response of 9.2 months. At the time of data cut-off, median follow-up time was 10 months and 48 patients remained on treatment.

In this phase 1/2 trial, the prevalence CNS metastases at baseline (57.5%) was higher than in the CROWN (26%) or ALEX (42%) trials. This is expected as almost all patients were receiving ficonalkib as a second or later line of therapy, and importantly, some patients had also received non-ALK-targeted treatments in the form of cytotoxic chemotherapy. The phase 1 trial of lorlatinib similarly had a higher percentage of patients with baseline CNS disease (72%) and demonstrated a 42% intracranial ORR in ALK⁺ patients (14), compared to the 37.5% intracranial ORR, including 4 (12.5%) complete responses, reported here.

In a post-hoc analysis of the phase 3 CROWN trial population, patients with CNS disease at baseline (n=38) were further evaluated and 23 (61%) had an intracranial complete response to lorlatinib; importantly; most of these patients were still receiving lorlatinib at the time of data cut-off (15). This excellent intracranial response to lorlatinib has set a standard of care for ALK⁺ patients.

Conclusions

Over the last decade, survival for patients with ALK-mutated NSCLC has improved significantly with the development of multiple lines of targeted therapy. As survival data on the newest licensed drugs continue to emerge, the true impact of new drugs takes longer to assess. Phase 1/2 data on ficonalkib demonstrate similar ORR and intracranial response rates to lorlatinib, with a different adverse events profile and could provide another third-generation TKI option.

Further data are required, from a global study, possibly with a head-to-head comparison to assess whether ficonalkib offers additional benefit over lorlatinib, or merely represents an additional drug option in the same space. Therefore, a phase 3 trial comparing both drugs would be the ideal design to assess if a specific TKI is superior in terms of PFS and/or OS. Given the emerging evidence of differential efficacy of ALK TKIs in patients with co-mutations and/or specific EML4-ALK variants, these could serve as stratifying factors to assess whether efficacy is higher in particular subgroups. Particular attention should be paid to the efficacy related to intracranial efficacy, both in patients with CNS metastatic disease at baseline, and those who develop CNS metastases later in their treatment pathway, as metastatic spread to the CNS is frequent in this population. In this early-phase trial, ficonalkib showed a response rate similar to that of other third-generation inhibitors.

In summary, ficonalkib is a third-generation ALK inhibitor with systemic and intracranial efficacy that appears comparable to lorlatinib, another third-generation inhibitor with regulatory approval. The key differentiating factor seems to be its toxicity profile, which may make it an appealing alternative for patients with cardiovascular and/or psychiatric comorbidities. However, to further improve patient outcomes, greater emphasis should be placed on developing new compounds that can overcome primary and acquired resistances, which ultimately lead to disease progression and negatively impact survival, rather than focusing on drugs with a similar activity spectrum.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-124/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-124/coif). I.G.R. reports consulting fees from Janssen. R.C. reports grants from Roche, AstraZeneca, Pfizer, Clovis, Lilly Oncology, MSD, BMS, Abbvie, Takeda, Janssen, Novartis; consulting fees from AstraZeneca, Boeringher Ingelheim, Lilly Oncology, Roche, Pfizer, MSD, BMS, Takeda, Janssen, Bayer, Novartis; and holds stock or stock options of The Christie Private Care. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-6. [Crossref] [PubMed]
2. Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013;31:1105-11. [Crossref] [PubMed]
3. Duruisseaux M, Besse B, Cadranel J, et al. Overall survival with crizotinib and next-generation ALK inhibitors in ALK-positive non-small-cell lung cancer (IFCT-1302 CLINALK): a French nationwide cohort retrospective study. Oncotarget 2017;8:21903-17. [Crossref] [PubMed]
4. Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol 2020;31:1056-64. [Crossref] [PubMed]
5. Kazandjian D, Blumenthal GM, Chen HY, et al. FDA approval summary: crizotinib for the treatment of metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements. Oncologist 2014;19:e5-11. [Crossref] [PubMed]
6. Hendriks LE, Kerr KM, Menis J, et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023;34:339-57. [Crossref] [PubMed]
7. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:829-38. [Crossref] [PubMed]
8. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2027-39. [Crossref] [PubMed]
9. Shaw AT, Bauer TM, de Marinis F, et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med 2020;383:2018-29. [Crossref] [PubMed]
10. Cooper AJ, Sequist LV, Lin JJ. Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management. Nat Rev Clin Oncol 2022;19:499-514. [Crossref] [PubMed]
11. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 2018;19:1654-67. [Crossref] [PubMed]
12. Shi Y, Hu X, Li X, et al. Ficonalkib (SY-3505) in Advanced ALK-Positive NSCLC: A Multicenter, Open-Label, Single-Arm, Phase 1/2 Study. J Thorac Oncol 2024;19:898-911. [Crossref] [PubMed]
13. Kurzrock R, Lin CC, Wu TC, et al. Moving Beyond 3+3: The Future of Clinical Trial Design. Am Soc Clin Oncol Educ Book 2021;41:e133-44. [Crossref] [PubMed]
14. Shaw AT, Felip E, Bauer TM, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol 2017;18:1590-9. [Crossref] [PubMed]
15. Solomon BJ, Bauer TM, Ignatius Ou SH, et al. Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients With ALK-Positive Advanced Non-Small-Cell Lung Cancer From the Phase III CROWN Study. J Clin Oncol 2022;40:3593-602. [Crossref] [PubMed]