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The lack of head-to-head randomised trials and the consequences for patients and national health service: The case of non-small cell lung cancer

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Abstract

Introduction

To introduce a drug to the market, it’s not mandatory for it to be more effective and safer than the current treatment for the same condition. Consequently, head-to-head studies between the two best treatments for the same condition are not required, and this could result in a lack of information for patients, clinicians, and decision-makers. This study aims to evaluate the presence of head-to-head studies among the drugs used for the treatment of non-small cell lung cancer (NSCLC).

Methods

Taking into account the National Comprehensive Cancer Network (NCCN) guidelines updated to 2022, which list all available treatments for each NSCLC subtype, the search engine Pubmed and the platform clinicaltrials.gov were consulted to find all completed and ongoing head-to-head studies among various treatments for NSCLC.

Results

Among the anti-EGFR (epidermal growth factor receptor) drugs, 7 studies were found, with 6 completed and 5 registrational for drug commercialisation. No completed study to date has compared osimertinib and afatinib. For anti-ALK (anaplastic lymphoma kinase) drugs, 7 studies were found, with 5 completed. Alectinib, brigatinib, and lorlatinib have no completed comparison studies, but all were compared with crizotinib. Among various immunotherapy-based regimens, 5 studies were found, with only 1 completed. Therapeutic regimens based on pembrolizumab, atezolizumab, or the combination of nivolumab/ipilimumab have not been compared in studies published to date.

Conclusion

There are few head-to-head studies comparing treatments for NSCLC; there are no such studies between the latest generation of drugs. Consequently, ambiguous areas exist due to the lack of comparative studies among the available evidence, preventing the clinician’s choice of the most effective treatment and risking the patient receiving suboptimal therapy. Simultaneously, the price of the drug cannot be determined correctly, relying only on indirect evaluations from different trials. To dispel this uncertainty, it would be desirable to initiate a process that brings together the demands derived from clinical practice and clinical research to provide clinicians and patients with the best possible evidence.

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References

  1. Sung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249

    Article  PubMed  Google Scholar 

  2. Falzone L, Salomone S, Libra M (2018) Evolution of cancer pharmacological treatments at the turn of the third millennium. Front Pharmacol 9:1300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Imyanitov EN, Iyevleva AG, Levchenko EV (2021) Molecular testing and targeted therapy for non-small cell lung cancer: current status and perspectives. Crit Rev Oncol Hematol 157:103194

    Article  PubMed  Google Scholar 

  4. Zhang Y, Zhang Z (2020) The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol 17(8):807–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ettinger DS, Wood DE, Aisner DL et al (2022) Non-small cell lung cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 20(5):497–530

  6. Reck M, Carbone DP, Garassino M, Barlesi F (2021) Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches. Annals Oncol 32(9):1101–1110

    Article  CAS  Google Scholar 

  7. Remon J, Hendriks LEL, Cardona AF, Besse B (2020) EGFR exon 20 insertions in advanced non-small cell lung cancer: a new history begins. Cancer Treat Rev 90:102105

    Article  CAS  PubMed  Google Scholar 

  8. Shaw AT, Engelman JA (2013) ALK in lung cancer: past, present, and future. J Clin Oncol 31(8):1105–1111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Leonetti A, Facchinetti F, Rossi G et al (2018) BRAF in non-small cell lung cancer (NSCLC): pickaxing another brick in the wall. Cancer Treat Rev 66:82–94

    Article  CAS  PubMed  Google Scholar 

  10. Bergethon K, Shaw AT, Ou SH et al (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30(8):863–870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Recondo G, Che J, Janne PA, Awad MM (2020) Targeting MET dysregulation in cancer. Cancer Discov 10(7):922–934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Harada G, Santini FC, Wilhelm C, Drilon A (2021) NTRK fusions in lung cancer: from biology to therapy. Lung Cancer 161:108–113

    Article  CAS  PubMed  Google Scholar 

  13. Belli C, Anand S, Gainor JF et al (2020) Progresses toward precision medicine in RET-altered solid tumors. Clin Cancer Res 26(23):6102–6111

    Article  CAS  PubMed  Google Scholar 

  14. Mazieres J, Drilon A, Lusque A et al (2019) Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Annal Oncol 30(8):1321–1328

    Article  CAS  Google Scholar 

  15. Lisberg A, Cummings A, Goldman JW et al (2018) A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naive patients with advanced NSCLC. J Thorac Oncol 13(8):1138–1145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gainor JF, Shaw AT, Sequist LV et al (2016) EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res 22(18):4585–4593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Felip E, Altorki N, Zhou C et al (2021) Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 398(10308):1344–1357

    Article  CAS  PubMed  Google Scholar 

  18. Akinboro O, Vallejo JJ, Nakajima EC et al (2022) Outcomes of anti–PD-(L)1 therapy with or without chemotherapy (chemo) for first-line (1L) treatment of advanced non–small cell lung cancer (NSCLC) with PD-L1 score ≥ 50%: FDA pooled analysis. J Clin Oncol 40(16_suppl):9000–9000

  19. Lasala R, Logreco A, Romagnoli A, Santoleri F, Musicco F, Costantini A (2020) Cancer drugs for solid tumors approved by the EMA since 2014: an overview of pivotal clinical trials. Eur J Clin Pharmacol 76(6):843–850

    Article  CAS  PubMed  Google Scholar 

  20. Hatswell AJ, Baio G, Berlin JA, Irs A, Freemantle N (2016) Regulatory approval of pharmaceuticals without a randomised controlled study: analysis of EMA and FDA approvals 1999–2014. BMJ Open 6(6):e011666

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ladanie A, Speich B, Briel M et al (2019) Single pivotal trials with few corroborating characteristics were used for FDA approval of cancer therapies. J Clin Epidemiol 114:49–59

    Article  PubMed  Google Scholar 

  22. Hilal T, Sonbol MB, Prasad V (2019) Analysis of control arm quality in randomized clinical trials leading to anticancer drug approval by the US Food and Drug Administration. JAMA Oncol 5(6):887–892

    Article  PubMed  PubMed Central  Google Scholar 

  23. Rossi A, Aimar G, Audisio M et al (2023) Analysis of the adequacy of control arms in oncology randomised clinical trials published between 2017 and 2021: a meta-research study. Eur J Cancer

  24. Del Fiol G, Workman TE, Gorman PN (2014) Clinical questions raised by clinicians at the point of care: a systematic review. JAMA Intern Med 174(5):710–718

    Article  PubMed  Google Scholar 

  25. Caldwell DM, Ades AE, Higgins JP (2005) Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 331(7521):897–900

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kim H, Gurrin L, Ademi Z, Liew D (2014) Overview of methods for comparing the efficacies of drugs in the absence of head-to-head clinical trial data. Br J Clin Pharmacol 77(1):116–121

    Article  PubMed  Google Scholar 

  27. Mills EJ, Thorlund K, Ioannidis JP (2013) Demystifying trial networks and network meta-analysis. BMJ 346:f2914

    Article  PubMed  Google Scholar 

  28. Ramalingam SS, Vansteenkiste J, Planchard D et al (2020) Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 382(1):41–50

    Article  CAS  PubMed  Google Scholar 

  29. Park K, Tan EH, O’Byrne K et al (2016) Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 17(5):577–589

    Article  CAS  PubMed  Google Scholar 

  30. Wu YL, Cheng Y, Zhou X et al (2017) Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 18(11):1454–1466

    Article  CAS  PubMed  Google Scholar 

  31. Nakagawa K, Garon EB, Seto T et al (2019) Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20(12):1655–1669

    Article  CAS  PubMed  Google Scholar 

  32. Seto T, Kato T, Nishio M et al (2014) Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol 15(11):1236–1244

    Article  CAS  PubMed  Google Scholar 

  33. Piccirillo MC, Bonanno L, Garassino MC et al (2022) Addition of Bevacizumab to Erlotinib as first-line treatment of patients with EGFR-mutated advanced nonsquamous NSCLC: the BEVERLY multicenter randomized phase 3 trial. J Thorac Oncol 17(9):1086–1097

    Article  CAS  PubMed  Google Scholar 

  34. Haratake N, Hayashi H, Shimokawa M et al (2022) Phase III clinical trial for the combination of Erlotinib plus Ramucirumab compared with Osimertinib in previously untreated advanced or recurrent non-small cell lung cancer positive for the L858R mutation of EGFR: REVOL858R (WJOG14420L). Clin Lung Cancer 23(3):e257–e263

    Article  CAS  PubMed  Google Scholar 

  35. Camidge DR, Kim HR, Ahn MJ et al (2018) Brigatinib versus Crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med 379(21):2027–2039

    Article  CAS  PubMed  Google Scholar 

  36. Shaw AT, Bauer TM, de Marinis F et al (2020) First-line Lorlatinib or Crizotinib in advanced ALK-positive lung cancer. N Engl J Med 383(21):2018–2029

    Article  CAS  PubMed  Google Scholar 

  37. Peters S, Camidge DR, Shaw AT et al (2017) Alectinib versus Crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 377(9):829–838

    Article  CAS  PubMed  Google Scholar 

  38. Hida T, Nokihara H, Kondo M et al (2017) Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 390(10089):29–39

    Article  CAS  PubMed  Google Scholar 

  39. Zhou C, Kim SW, Reungwetwattana T et al (2019) Alectinib versus crizotinib in untreated Asian patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALESIA): a randomised phase 3 study. Lancet Respir Med 7(5):437–446

    Article  CAS  PubMed  Google Scholar 

  40. Popat S, Liu G, Lu S, Song G, Ma X, Yang JC (2021) Brigatinib vs alectinib in crizotinib-resistant advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALTA-3). Future Oncol 17(32):4237–4247

    Article  CAS  PubMed  Google Scholar 

  41. Targeted treatment for ALK positive patients who have previously been treated for non-squamous non-small cell lung cancer. https://classic.clinicaltrials.gov/ct2/show/NCT03737994. Published 2023. Updated 14 Apr 2023. Accessed 7 Aug 2023

  42. Socinski MA, Jotte RM, Cappuzzo F et al (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378(24):2288–2301

    Article  CAS  PubMed  Google Scholar 

  43. Frost N, Bleckmann A, Griesinger F et al (2023) Rationale and design of the phase II ANTELOPE study of Atezolizumab, Carboplatin and nab-Paclitaxel vs. Pembrolizumab, platinum and pemetrexed in TTF-1 negative, metastatic lung adenocarcinoma (AIO-TRK-0122). Clin Lung Cancer

  44. Immune profile selection by fraction of ctDNA in patients with advanced NSCLC treated with immunotherapy (G360-IIT). https://classic.clinicaltrials.gov/ct2/show/NCT05715229. Published 2023. Updated 6 Jul 2023. Accessed 2023

  45. Testing the effects of MK-3475 (Pembrolizumab) with or without the usual chemotherapy treatment for patients 70 years of age and older with advanced non-small cell lung cancer. https://classic.clinicaltrials.gov/ct2/show/NCT04533451. Published 2023. Updated 18 Apr 2023. Accessed Aug 2023

  46. Shiraishi Y, Hakozaki T, Nomura S et al (2022) A multicenter, randomized phase III study comparing platinum combination chemotherapy plus pembrolizumab with platinum combination chemotherapy plus Nivolumab and Ipilimumab for treatment-naive advanced non-small cell lung cancer without driver gene alterations: JCOG2007 (NIPPON Study). Clin Lung Cancer 23(4):e285–e288

    Article  CAS  PubMed  Google Scholar 

  47. Pemetrexed-free vs. Pemetrexed-based immunochemotherapy in metastatic TTF-1 negative lung adenocarcinoma (ANTELOPE). https://classic.clinicaltrials.gov/ct2/show/NCT05689671. Published 2023. Updated 19 Jan 2023. Accessed Aug 2023

  48. Vokinger KN, Glaus CEG, Kesselheim AS, Serra-Burriel M, Ross JS, Hwang TJ (2023) Therapeutic value of first versus supplemental indications of drugs in US and Europe (2011–20): retrospective cohort study. BMJ 382:e074166

    Article  PubMed  PubMed Central  Google Scholar 

  49. Garattini S, Bertele V (2007) How can we regulate medicines better? BMJ 335(7624):803–805

    Article  PubMed  PubMed Central  Google Scholar 

  50. Wieseler B (2023) Patients need better treatments, not just more of the same. BMJ 382:1466

    Article  PubMed  Google Scholar 

  51. Naci H, Salcher-Konrad M, Kesselheim AS et al (2020) Generating comparative evidence on new drugs and devices before approval. Lancet 395(10228):986–997

    Article  PubMed  Google Scholar 

  52. Flacco ME, Manzoli L, Boccia S et al (2015) Head-to-head randomized trials are mostly industry sponsored and almost always favor the industry sponsor. J Clin Epidemiol 68(7):811–820

    Article  PubMed  Google Scholar 

  53. West HJ (2023) Clinical decision making in the real world-the perfect as the enemy of the good. JAMA Oncol

  54. (EMA) EMA. Data analysis and real world interrogation network (DARWIN EU). https://www.ema.europa.eu/en/about-us/how-we-work/big-data/data-analysis-real-world-interrogation-network-darwin-eu. Published 2023. Accessed 7 Aug 2023

  55. (FDA) USFDA. Real-world evidence. https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence. Published 2023. Updated 2 May 2023. Accessed 7 Aug 2023

  56. IQVIA (2023) Global oncology trends. https://www.iqvia.com/insights/the-iqvia-institute/reports/global-oncology-trends-2023. Published 2023. Updated 24 May 2023. Accessed 7 Aug 2023

  57. Del Paggio JC, Sullivan R, Schrag D et al (2017) Delivery of meaningful cancer care: a retrospective cohort study assessing cost and benefit with the ASCO and ESMO frameworks. Lancet Oncol 18(7):887–894

    Article  PubMed  Google Scholar 

  58. Cohen D (2017) Cancer drugs: high price, uncertain value. BMJ 359:j4543

    Article  PubMed  PubMed Central  Google Scholar 

  59. Angelis A, Polyakov R, Wouters OJ, Torreele E, McKee M (2023) High drug prices are not justified by industry’s spending on research and development. BMJ 380:e071710

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Hospital Pharmacy of Corato, Local Health Unit of Bari, Corato, Italy

    Ruggero Lasala

  2. Territorial Pharmaceutical Service, Local Health Unit of Lanciano Vasto Chieti, Chieti, Italy

    Alessia Romagnoli

  3. Hospital Pharmacy, Santo Spirito Hospital, Pescara, Italy

    Fiorenzo Santoleri & Alberto Costantini

  4. Hospital Pharmacy Complex Operational Unit, Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello, Palermo, Italy

    Valentina Isgrò & Piera Polidori

  5. UOC Farmacia Ospedaliera, Direzione Tecnica Farmacia, AUSL Piacenza, Piacenza, Italy

    Corrado Confalonieri

  6. Candiolo Cancer Institute, Fondazione del Piemonte per l’Oncologia - IRCCS, Candiolo, Italy

    Fiorenza Enrico

  7. Medical Oncology, Santo Spirito Hospital, Pescara, Italy

    Gianluca Russo, Alessandra Di Paolo, Francesco Malorgio & Giordano Beretta

  8. Hospital Pharmacy, IRCCS Regina Elena National Cancer Institute, Rome, Italy

    Felice Musicco

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  1. Ruggero Lasala
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Contributions

Ruggero Lasala and Felice Musicco contributed to the conception and design of the study; Ruggero Lasala, Alessia Romagnoli, Felice Musicco wrote the main manuscript; Ruggero Lasala, Alessia Romagnoli, Fiorenzo Santoleri, Valentina Isgrò, Corrado Confalonieri, Alberto Costantini, Fiorenza Enrico, Gianluca Russo, Felice Musicco contributed to the acquisition, analysis of the data; Ruggero Lasala, Alessia Romagnoli, Fiorenzo Santoleri, Valentina Isgrò, Corrado Confalonieri, Alberto Costantini, Fiorenza Enrico, Gianluca Russo, Piera Polidori, Alessandra Di Paolo, Francesco Malorgio, Giordano Beretta and Felice Musicco contributed to interpretation of data, reviewed and gave the final approval to the manuscript.

Corresponding author

Correspondence to Ruggero Lasala.

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Ethical approval

Considering that our study relies upon data relating to previously published clinical trials and did Fnot require patient involvement, we did not solicit an opinion from the Hospital Ethics Committee nor did we require the collection of informed consent from patients.

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The authors declare no competing interests.

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Lasala, R., Romagnoli, A., Santoleri, F. et al. The lack of head-to-head randomised trials and the consequences for patients and national health service: The case of non-small cell lung cancer. Eur J Clin Pharmacol 80, 519–527 (2024). https://doi.org/10.1007/s00228-024-03628-2

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