ALKTERNATE: A Pilot Study Alternating Lorlatinib With Crizotinib in ALK-Positive NSCLC With Prior ALK Inhibitor Resistance

Malinda Itchins^{1

2

3}, Shirley Liang¹, Chris Brown⁴, Tristan Barnes⁵, Gavin Marx^{6

7}, Venessa Chin^{8

9

10}, Steven Kao^{3

11}, Po Yee Yip^{12

13}, Antony J Mersiades^{4

5}, Adnan Nagrial^{14

15

16}, Victoria Bray¹⁷, Geoffrey Peters^{18

19}, Sagun Parakh^{20

21}, Kavita Garg²², Bob T Li²³, Matthew McKay²⁴, Kenneth O'Byrne²⁵, Thomas John^{26

27}, Anthony J Gill^{1

2}, Mark P Molloy^{2

24}, Benjamin J Solomon^{26

27}, Nick Pavlakis^{1

2}

Affiliations

¹ Royal North Shore Hospital, St Leonards, Australia.
² Northern Clinical School, University of Sydney, St Leonards, Australia.
³ Chris O'Brien Lifehouse, Camperdown, Australia.
⁴ NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia.
⁵ Northern Beaches Hospital, Frenchs Forest, Australia.
⁶ Sydney Adventist Hospital, Wahroonga, Australia.
⁷ Australian National University, Sydney, Australia.
⁸ The Kinghorn Cancer Centre, St Vincent's Hospital Sydney, Darlinghurst, Australia.
⁹ The Garvan Institute of Medical Research, Darlinghurst, Australia.
¹⁰ University of New South Wales, Darlinghurst, Australia.
¹¹ Sydney Medical School, University of Sydney, Camperdown, Australia.
¹² Macarthur Cancer Therapy Centre, Campbelltown Hospital, Campbelltown, Australia.
¹³ School of Medicine, Western Sydney University, Campbelltown, Australia.
¹⁴ Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia.
¹⁵ Blacktown Hospital, Blacktown, Australia.
¹⁶ Westmead Clinical School, University of Sydney, Westmead, Australia.
¹⁷ Liverpool Hospital, Liverpool, Australia.
¹⁸ Canberra Hospital, Canberra, Australia.
¹⁹ Australian National University, Canberra, Australia.
²⁰ Olivia Newton-John Cancer Research Institute, Austin Hospital, Heidelberg, Australia.
²¹ School of Cancer Medicine, La Trobe University, Bundoora, Australia.
²² Resolution Bioscience, Kirkland, Washington.
²³ Memorial Sloan Kettering Cancer Center, New York, New York.
²⁴ Kolling Institute, University of Sydney, St Leonards, Australia.
²⁵ Princess Alexandra Hospital, Woolloongabba, Australia.
²⁶ Peter MacCallum Cancer Centre, Melbourne, Australia.
²⁷ University of Melbourne, Melbourne, Australia.

PMID: 39309618
PMCID: PMC11416292
DOI: 10.1016/j.jtocrr.2024.100703

ALKTERNATE: A Pilot Study Alternating Lorlatinib With Crizotinib in ALK-Positive NSCLC With Prior ALK Inhibitor Resistance

Malinda Itchins et al. JTO Clin Res Rep. 2024.

. 2024 Jul 8;5(9):100703.

doi: 10.1016/j.jtocrr.2024.100703. eCollection 2024 Sep.

Authors

Affiliations

¹ Royal North Shore Hospital, St Leonards, Australia.
² Northern Clinical School, University of Sydney, St Leonards, Australia.
³ Chris O'Brien Lifehouse, Camperdown, Australia.
⁴ NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia.
⁵ Northern Beaches Hospital, Frenchs Forest, Australia.
⁶ Sydney Adventist Hospital, Wahroonga, Australia.
⁷ Australian National University, Sydney, Australia.
⁸ The Kinghorn Cancer Centre, St Vincent's Hospital Sydney, Darlinghurst, Australia.
⁹ The Garvan Institute of Medical Research, Darlinghurst, Australia.
¹⁰ University of New South Wales, Darlinghurst, Australia.
¹¹ Sydney Medical School, University of Sydney, Camperdown, Australia.
¹² Macarthur Cancer Therapy Centre, Campbelltown Hospital, Campbelltown, Australia.
¹³ School of Medicine, Western Sydney University, Campbelltown, Australia.
¹⁴ Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia.
¹⁵ Blacktown Hospital, Blacktown, Australia.
¹⁶ Westmead Clinical School, University of Sydney, Westmead, Australia.
¹⁷ Liverpool Hospital, Liverpool, Australia.
¹⁸ Canberra Hospital, Canberra, Australia.
¹⁹ Australian National University, Canberra, Australia.
²⁰ Olivia Newton-John Cancer Research Institute, Austin Hospital, Heidelberg, Australia.
²¹ School of Cancer Medicine, La Trobe University, Bundoora, Australia.
²² Resolution Bioscience, Kirkland, Washington.
²³ Memorial Sloan Kettering Cancer Center, New York, New York.
²⁴ Kolling Institute, University of Sydney, St Leonards, Australia.
²⁵ Princess Alexandra Hospital, Woolloongabba, Australia.
²⁶ Peter MacCallum Cancer Centre, Melbourne, Australia.
²⁷ University of Melbourne, Melbourne, Australia.

PMID: 39309618
PMCID: PMC11416292
DOI: 10.1016/j.jtocrr.2024.100703

Abstract

Introduction: ALK-positive lung cancers represent a molecularly diverse disease. With drug exposure, driving selection pressure, and resistance pathways, disease relapse will emerge. There is compelling rationale to investigate novel treatment strategies, informed by dynamic circulating tumor DNA (ctDNA) monitoring.

Methods: The single-arm, pilot study ALKTERNATE investigated fixed alternating cycles of lorlatinib intercalated with crizotinib in individuals resistant to second-generation ALK inhibitors. Dynamic ctDNA explored the correlation with disease response and disease recurrence and defined disease resistance. The primary outcome was time-to-treatment failure, a composite of tolerability, feasibility, and efficacy. Secondary outcomes included standard survival measures, toxicity, pharmacokinetic analysis, and patient-reported outcomes. Tertiary outcomes were proteogenomic analyses of tissue and plasma.

Results: A total of 15 individuals were enrolled; three encountered primary resistance to lorlatinib induction. There were 12 participants who received alternating therapy, and this approach revealed safety, feasibility, and effectiveness. Patient-reported outcomes were maintained or improved on therapy, and toxicity was consistent with previous reports. The pharmacokinetic measures were similar to the single-arm drug experience. Median time-to-treatment failure was 10 months; overall survival was 23 months. ctDNA profiles indicated inferior survival in those with preexistent TP53 mutations and those without clear or cleared ctDNA at trial induction. The study defined a vastly heterogeneous population with an abundance of ALK coexisting with non-ALK resistance variants.

Conclusions: ALKTERNATE revealed feasibility with a novel alternating ALK inhibitor strategy in ALK-positive NSCLC. Results support progressing inquiry into this approach and propose a flexible design with drug(s) selected and alternating time frames, informed by real-time plasma profiling. Moving this concept to treatment naive may also optimize impact.

Keywords: ALK; ALKi; Crizotinib; Lorlatinib; NSCLC; Resistance; ctDNA.

PubMed Disclaimer

Conflict of interest statement

ALKTERNATE received grant funding and provision of drug from Pfizer. The following authors have received personal financial payment from Pfizer for consultancy and/or honoraria: MI, AN, SK, AM, BJS, NP.

Figures

**Figure 1**
Consort diagram of patient screening, accrual, and progress on the study. ∗Two patients were deemed trial ineligible at the TMC discretion due to baseline ctDNA indicating disease unlikely *ALK* driven: ALK01-04 plasma, 10 variants detected, no ALK-fusion; ALK01-11 *KRAS* G12C detected, confirmed on tissue biopsy, no *ALK* fusion. ˆThree patients with primary resistance to lorlatinib harbored an *EML4-ALK* V1, two with co-occurring *TP53* in the plasma and tissue, and one with *MYC* CNG present in tissue biopsy (ALK01-17). ctDNA, circulating tumor DNA; TMC, trial management committee.

**Figure 2**
Swimmer plot of participants and treatments received and duration of treatment benefit before and after study commencement (y = 0 is ALKTERNATE trial commencement).

**Figure 3**
Kaplan-Meir survival plots. (A) Time-to-treatment failure for alternating therapy; (B) overall survival in all enrolled; (C) progression free survival in all enrolled; (D) progression-free survival based on *TP53* trial entry status; and (E) progression-free survival in those with clear ctDNA at trial entry or after one cycle of alternating treatment versus those with persisting detectable ctDNA. ctDNA, circulating tumor DNA. ctDNA, circulating tumor DNA.

**Figure 4**
Qualitative ctDNA and the frequency of variant capture (A) for the ALK fusion variant, (B) ALK mutations detected in the blood and frequency across individuals, (C) non-ALK variants detected in the blood and frequency across individuals, and (D–H) five individual patient temporal ctDNA allelic frequency plots revealing variant quantitatively. CNG is not captured in VAF plots presented, (D). Harbored *MET* CNG at baseline (6 copies) and PD continuous lorlatinib (four copies). ctDNA, circulating tumor DNA.

See this image and copyright information in PMC

References

1. Soda M., Choi Y.L., Enomoto M., et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–566. - PubMed
1. Solomon B.J., Mok T., Kim D.W., et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–2177. - PubMed
1. Peters S., Camidge D.R., Shaw A.T., et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377:829–838. - PubMed
1. Camidge D.R., Kim H.R., Ahn M.J., et al. Brigatinib versus crizotinib in ALK-Positive non-small-cell lung cancer. N Engl J Med. 2018;379:2027–2039. - PubMed
1. Shaw A.T., Bauer T.M., de Marinis F., et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383:2018–2029. - PubMed

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States

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ALKTERNATE: A Pilot Study Alternating Lorlatinib With Crizotinib in ALK-Positive NSCLC With Prior ALK Inhibitor Resistance

Affiliations

ALKTERNATE: A Pilot Study Alternating Lorlatinib With Crizotinib in ALK-Positive NSCLC With Prior ALK Inhibitor Resistance

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding