Project Optimus and Its Impact on the Oncology Treatment Landscape

Cancer remains a devastating disease that accounts for more than 600,000 deaths annually in the United States. First introduced in the 1940s, cytotoxic chemotherapy continues to be the cornerstone of treatment for various malignancies. Historical studies across these different malignancies have demonstrated a clear dose-response relationship for these agents. Namely, higher doses or shorter dosing intervals often lead to improved anticancer efficacy, resulting in the long-standing belief that "more is more” in oncology.^1,2

However, these cytotoxic agents have a narrow therapeutic window, with higher efficacious doses also resulting in more substantial treatment-related toxicities. As such, the traditional method for evaluating new cytotoxic agents focuses on identifying the maximum tolerated dose (MTD), which is used in subsequent dose expansion and registrational studies.³

Over the past 2 decades, the therapeutic landscape of oncology has shifted with the introduction of novel therapies such as tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors, and antibody-drug conjugates (ADCs). These therapies possess distinct mechanisms of action compared with traditional cytotoxic chemotherapy. In addition, they have a wider therapeutic index with efficacy observed at doses far lower than the MTD, sometimes without an MTD being identified at all.

For example, in the initial phase 1 dose finding study (NCT01802632)⁴ of osimertinib (AZD9291 Tagrisso; AstraZeneca)—a potent, selective, irreversible EGFR-targeting TKI—in patients with advanced or metastatic EGFR-mutant non–small cell lung cancer (NSCLC) after progression on prior TKI, investigators did not observe any dose-limiting toxicities across their entire dose range of 20 to 240 mg daily. However, similar overall response rates (ORR) were observed in patients regardless of the osimertinib dose (20 mg: 52%; 40 mg: 43%; 80 mg: 52%; 160 mg: 58%; 24 mg: 52%).⁵

With targeted therapies, the durability of response may also not correlate with treatment dose. In the phase 3 CROWN study (NCT03052608)⁶ of first-line lorlatinib (Lorbrena; Pfizer) in patients with advanced/metastatic ALK-rearranged NSCLC, dose reductions within the first 16 weeks of therapy did not impact intracranial or overall progression-free survival (PFS).⁷ This lack of dose-response relationship has also been demonstrated in prospective and retrospective studies of ribociclib (Kisqali; Novartis; MONALEESA-2 [NCT01958021], MONALEESA-3 [NCT02422615], and MONALEESA-7 [NCT02278120])^8-10 and palbociclib (Ibrance; Pfizer, Inc; NCT05361655),¹¹ respectively, in breast cancer.^12,13 These studies even demonstrated numerically better PFS and overall survival (OS) in patients who underwent a dose reduction.

Similarly, immune checkpoint inhibitor efficacy may not be correlated with dose. In the phase 3 trial (KEYNOTE-010; NCT01905657)¹⁴ of subsequent line pembrolizumab (Keytruda; Merck) in NSCLC, patients were randomly assigned to receive 1 of 2 different doses of pembrolizumab (2 mg/kg or 10 mg/kg) or docetaxel. Despite a 5-fold increase in dose, OS was similar between the 2 pembrolizumab doses (HR, 1.12, 0.77-1.62 [95% CI]).¹⁵ These are just a few of the many examples that exist in oncology, calling into whether more is actually more.¹⁶
Recognizing this gap, the FDA launched Project Optimus in 2021 to modernize dose-finding strategies for oncology drugs. This initiative was catalyzed by the registrational trial (NCT03600883)¹⁷ of sotorasib (Lumakras, Amgen, Inc), the first commercially approved KRAS inhibitor, in which a nonlinear relationship between dose, exposure, and clinical efficacy was observed.¹⁸

Across the dosing range of 180 to 960 mg, systemic sotorasib exposure was remarkably similar with no clear pattern demonstrated between drug dose and various pharmacokinetic parameters or treatment response (Table).

Furthermore, sotorasib exposure appeared to be inversely related to clinical efficacy, where patients in the highest quartile of drug exposure had lower ORR, median PFS (mPFS), and median OS compared with those with lower drug exposure (Figures A, B, and C). The data led the FDA reviewers to conclude that the “FDA does not consider the proposed [sotorasib] dosage of 960 mg [daily] to be optimized based on the following PK [pharmacokinetic] and efficacy/safety data.”¹⁸

Through collaborations with patients, investigators, and professional societies such as the American Association for Cancer Research and the American Society of Clinical Oncology, the FDA finalized guidance to inform sponsors on how to approach dose optimization throughout the drug development process. The recent approvals for tarlatamab (Imdelltra; Amgen), trastuzumab-deruxtecan (T-DXd, Enhertu; Daiichi Sankyo and AstraZeneca), and sunvozertinib (Zegfrovy; Dizal Pharmaceutical) exemplify the shift in drug development and regulatory decisions following the launch of Project Optimus.¹⁹

Tarlatamab is a bispecific T-cell engager targeting DLL3 on tumor cells and CD3 on T cells, which was approved in 2024 based on the findings of the DeLLphi-301 study (NCT05060016).^20,21 In this trial, 2 doses were studied (10 and 100 mg), which demonstrated similar efficacy (ORR: 40% with 10 mg; 32% with 100 mg; mPFS: 4.9 months at 10 mg, 3.9 months at 100 mg) with significant differences in toxicities (cytokine release syndrome: 51% at 10 mg; 61% at 100 mg; ICANS: 8% at 10 mg, 28% at 100 mg), leading to the FDA approval of the lower 10 mg dose.

T-DXd is an ADC consisting of a HER2 monoclonal antibody, a topoisomerase 1 inhibitor payload, and a tetrapeptide-based cleavable linker that was initially approved in 2019 for the treatment of HER2-positive breast cancer. The DESTINY-Lung01 trial (NCT03505710)²² demonstrated promising efficacy when used at a dose of 6.4mg/kg for HER2-mutant NSCLC. However, toxicity at this dose was concerning, particularly the 26% incidence of drug-induced interstitial lung disease.²³

In the subsequent dose-finding study DESTINY-Lung02 (NCT04644237),²⁴ similar efficacy (ORR: 50% vs 56%; mPFS: 10.0 vs 12.9 months; mOS: 19.0 vs 17.3 months) was observed at the lower dose (5.4 mg/kg vs 6.4 mg/kg) with substantially lower rates of grade 3 or higher treatment-related adverse effects (40% vs 60%) and drug-induced pneumonitis (15% vs 32%).²⁵ This led to the FDA approval of the lower 5.4 mg/kg dose for HER2-mutant NSCLC.

Lastly, sunvozertinib is an EGFR TKI with activity in patients harboring an EGFR exon 20 insertion mutation. This was initially approved in China for this indication in 2023 at a dose of 300 mg daily based on the findings from the WU-KONG6 study (NCT05712902).²⁶

The global registrational study WU-KONG1B (NCT03974022)²⁷ examined both a 200 and 300 mg dose and found similar efficacy across both doses (ORR: 46% vs 46%, median duration of response: 11.1 vs 9.8 months) with substantially lower rates of grade 3 or higher diarrhea with the lower dose (2.2% vs 21%).²⁸ Again, this led to the approval of the lower 200 mg dose in the US as compared with the higher dose in China. As efforts aimed at dose optimization have increased, newly approved treatments can offer patients a similar level of anticancer effect with a significant reduction in toxicity burden.

Together, these examples highlight the importance of aligning dose-finding strategies with the unique pharmacology of modern cancer therapies. With the advent of novel antineoplastic treatments, we have been able to substantially improve outcomes across nearly every type of malignancy. Project Optimus has been a much-needed paradigm shift to ensure our drug-development process aligns with the mechanisms of action of our novel therapies to ultimately provide both the most efficacious and safest treatments for our patients with cancer. This will allow patients to successfully remain on therapy for longer and maintain their quality of life while they are receiving cancer-directed treatment. Although Project Optimus aims to provide guidance during the preregistrational phase, it also highlights the need for ongoing investigation of optimal doses in real-world patients.

REFERENCES
1. Bonadonna G, Valagussa P. Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med. 1981;304(1):10-15. doi:10.1056/NEJM198101013040103

2. Womer RB, West DC, Kralio MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2012;30(33):4148-4154. doi:10.1200/JCO.2011.41.5703
3. Wong HH, Halford, S. Dose-limiting toxicity and maximum tolerated dose: still fit for purpose? Lancet Oncol. 2015;16(13):1287-1288. doi:10.1016/S1470-2045(15)00248-X
4. AZD9291 First time in patients ascending dose study (AURA). ClinicalTrials.gov. Updated January 18, 2024. Accessed October 14, 2025. https://clinicaltrials.gov/study/NCT01802632
5. Jänne PA, Yang JCH, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689-1699. doi:10.1056/NEJMoa1411817
6. A study of lorlatinib versus crizotinib in first line treatment of patients with ALK-positive NSCLC. ClinicalTrials.gov. Updated December 24, 2024. Accessed October 14, 2025. https://clinicaltrials.gov/study/NCT03052608
7. 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.24.0058
8. Study of efficacy and safety of LEE011 in postmenopausal women with advanced breast cancer (MONALEESA-2). ClinicalTrials.gov. Updated March 7, 2025. Accessed October 14, 2025. https://clinicaltrials.gov/study/NCT01958021
9. Study of efficacy and safety of LEE011 in men and postmenopausal women with advanced breast cancer. (MONALEESA-3). ClinicalTrials.gov. Updated November 30, 2023. Accessed October 14, 2025. https://clinicaltrials.gov/study/NCT02422615
10. Study of efficacy and safety in premenopausal women with hormone receptor positive, HER2-negative advanced breast cancer (MONALEESA-7). ClinicalTrials.gov. March 12, 2024. Accessed October 14, 2025. https://clinicaltrials.gov/study/NCT02278120
11. Real-world effectiveness of palbociclib in combination with an aromatase inhibitor. ClinicalTrials.gov. Updated June 7, 2024. Accessed October 14, 2025. https://clinicaltrials.gov/study/NCT05361655
12. Burris HA, Chan A, Bardia A, et al. Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive, HER2-negative advanced breast cancer. Br J Cancer. 2021; 125(5):679-686. doi: 10.1038/s41416-021-01415-9
13. Layman RM, Liu X, Li B, McRoy L, Brufsky A. Real-world palbociclib dose modifications and clinical outcomes in patients with HR+/HER2- metastatic breast cancer: a Flatiron Health database analysis. Breast. 2025;81:104448. doi:10.1016/j.breast.2025.104448
14. Study of two doses of pembrolizumab (MK-3475) versus docetaxel in previously treated participants with non-small cell lung cancer (MK-3475-010/KEYNOTE-010). ClinicalTrials.gov. Updated October 6, 2021. Accessed October 14, 2025. https://clinicaltrials.gov/study/NCT01905657
15. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550. doi:10.1016/S0140-6736(15)01281-7
16. Shah M, Rahman A, Theoret MR, Pazdur R. The drug-dosing conundrum in oncology - when less is more. N Engl J Med. 2021;385(16):1445-1447. doi:10.1056/NEJMp2109826
17. A phase 1/2, study evaluating the safety, tolerability, PK, and efficacy of sotorasib (AMG 510) in subjects with solid tumors with a specific KRAS mutation (CodeBreaK 100). ClinicalTrials.gov. Updated October 7, 2025. Accessed October 14, 2025. https://clinicaltrials.gov/study/NCT03600883
18. Center for Drug Evaluation and Research. Application number 214665Orig1s000, multi-discipline review. Accessed August 15, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214665Orig1s000MultidisciplineR.pdf
19. Guidance document: optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases. FDA. August 2024. Accessed August 15, 2025. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases
20. Ahn MJ, Cho BC, Felip E, et al; for the DeLLphi-301 Investigators. Tarlatamab for patients with previously treated small-cell lung cancer. N Engl J Med. 2023;389(22):2063-2075. doi:10.1056/NEJMoa230798
21. A phase 2 study of tarlatamab in patients with small cell lung cancer (SCLC) (DeLLphi-301). ClinicalTrials.gov. Updated November 10, 2025. Accessed November 12, 2025. https://clinicaltrials.gov/study/NCT05060016
22. DS-8201a in human epidermal growth factor receptor 2 (HER2)-expressing or -mutated non-small cell lung cancer (DESTINY-Lung01). ClinicalTrials.gov. Updated May 30, 2025. https://clinicaltrials.gov/study/NCT03505710
23. Li BT, Smit EF, Goto Y, et al; for the DESTINY-Lung01 Trial Investigators. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2021;386(3):241-251. doi:10.1056/NEJMoa2112431
24. Trastuzumab deruxtecan in participants with HER2-mutated metastatic non-small cell lung cancer (NSCLC) (DESTINY-LUNG02). ClinicalTrials.gov. October 24, 2024. Accessed October 14, 2025. https://www.clinicaltrials.gov/study/NCT04644237
25. Jänne PA, Goto Y, Kubo T, et al. Final analysis results and patient-reported outcomes from DESTINY-Lung02-a dose-blinded, randomized, phase 2 study of trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small cell lung cancer. J Thorac Oncol. Published online July 30, 2025. doi:10.1016/j.jtho.2025.07.129
26. Sunvozertinib (DZD9008) in pretreated lung cancer patients with EGFR exon20 insertion mutation (WU-KONG6). ClinicalTrials.gov. Updated December 30, 2024. https://clinicaltrials.gov/study/NCT05712902
27. Assessing an oral EGFR inhibitor, sunvozertinib in patients who have advanced non-small cell lung cancer with EGFR or HER2 mutation (WU-KONG1). ClinicalTrials.gov. Updated February 28, 2025. Accessed October 14, 2025. https://www.clinicaltrials.gov/study/NCT03974022
28. Center for Drug Evaluation and Research. Application number 219839Orig1s000, multi-discipline review. Accessed August 15, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2025/219839Orig1s000MultidisciplineR.pdf