Winning the war against cancer in the precision era: it’s about time

Recently, Sheng et al. published the groundbreaking RC48-CO16 trial¹ in the New England Journal of Medicine; it showed that the combination of disitamab vedotin and toripalimab significantly improved median progression free survival (PFS) (13.1 versus 6.5 months (hazard ratio 0.36, P < 0.001)) and overall survival (OS) (31.5 versus 16.9 months (hazard ratio 0.54, P < 0.001)) compared with standard-of-care chemotherapy in patients with treatment-naive HER2-expressing, unresectable, locally advanced or metastatic urothelial carcinoma. This regimen may bring about a paradigm shift in the first-line management of HER2-expressing urothelial cancer, and these results underscore a fundamental yet often overlooked tenet in oncology--the timing of effective treatment is crucial.

Perhaps the posterchild for the importance of early therapy is chronic myelogenous leukemia (CML). The hallmark of CML is the Bcr-Abl alteration resulting in aberrant tyrosine kinase enzymatic activity²; CML has transformed from a lethal disease with patients dying within 3–4 years to one with a near-normal life expectancy because of drugs such as imatinib, which target the aberrant Bcr-Abl kinase activity.³ However, imatinib given in the late stages of CML has marginal activity and impact on survival; in contrast, imatinib administered to patients with newly diagnosed CML results in near-100% complete remission rates and near-normal life expectancy. The rapidly diminishing impact of imatinib on later disease is almost certainly due to clonal evolution. Even so, the lessons of CML have largely been lost in the solid tumor field, with most precision therapies persistently applied late in the disease.⁴

The RC48-C016 trial¹ demonstrates that a strong, precise first line of defense is the most effective way to combat cancer. The study achieved notable survival outcomes by advancing a highly effective targeted combination to first-line treatment for a biomarker-selected cohort (HER2-expressing tumors, which constitute 52–70% of urothelial cancers). The multidirectional tumor activity of disitimab (a novel HER2-targeted antibody-drug conjugate (ADC) with the monomethyl auristatin E (MMAE) payload) and toripalimab (anti-PD1) combination helps mitigate challenges presented by biomarker heterogeneity, dynamic target loss, and other resistance mechanisms.

It is worth noting that 82.6% of the screened patients exhibited HER2 expression [1+ to 3+ on immunohistochemistry (IHC)]. The clinical outcomes were better in HER2 IHC 2 + /3+ vs IHC 1+ patients. However, it was unclear if IHC3 + patients benefited more than IHC 2 + . The ADC and checkpoint inhibitor combination engage cancer and immune effector cells through multiple mechanisms, including immunogenic cell death, antibody-dependent cell mediated cytotoxicity, and dendritic cell activation, thereby enhancing the tumor response. The multidirectional tumor activity of combination therapies also helps mitigate challenges posed by resistance clones and bypass pathways (Fig. 1).

Fig. 1.

Early Integration of HER2-Targeted Therapy Combinations. The clock symbolizes the critical aspect of timing. Multi-modal mechanism of action of a novel HER2-based antibody drug conjugate in combination with an immune checkpoint inhibitor, demonstrating simultaneous targeting of HER2-expressing cancer cells via diverse pathways, including receptor blockade through an antibody, payload-induced cytotoxicity, and immune cell redirection. Early integration of this strategy in treatment algorithms may improve clinical outcomes by intervening when tumor burden is low, immune function is preserved, and resistance mechanisms have not yet emerged. “Created through Biorender.com”

The effectiveness of first-line therapy with immune checkpoint inhibitors has recently been demonstrated by Cercek and colleagues in microsatellite-unstable solid tumors treated in the neoadjuvant setting. Among 117 patients with various cancers (most commonly colorectal cancer) treated with the anti-PD1 antibody dostarlimab, recurrence-free survival at two years was an impressive 92%, obviating the need for surgery, radiation, and chemotherapy.⁵ Therefore, immunotherapy, in a manner similar to gene targeted therapy, may be markedly more effective in newly diagnosed disease, perhaps because the immune system has not been damaged by cytotoxic agents, there is better blood supply allowing more effective immune cell trafficking, the antigen-presenting machinery has not been downregulated, and the tumor burden is lower.

The RC48-C016 results¹ are especially interesting because of the combination of HER2-targeted therapy with immune checkpoint inhibition. ADCs targeting HER2 not only kill HER2-expressing tumor cells directly but also induce immunogenic cell death, releasing tumor antigens that can be recognized by PD-1 blockade. This logical combination strategy targets both the oncogenic driver and the tumor microenvironment. It may work best when the tumor burden is low and immune surveillance remains intact.

Common side effects of the experimental arm were elevated aminotransferase levels and peripheral neuropathy. They were mostly grade 1–2; the tolerability of a potentially chemotherapy-free combination is important because it allows patients to receive an effective treatment regimen without the cumulative toxicity that often limits the duration of chemotherapy. It can also be an effective strategy to treat elderly, frail, or platinum-ineligible patients who suffer from HER2-expressing bladder cancer. Some key considerations that may affect its implementation in clinic include lack of standardization of HER2 testing methodologies, comparative effectiveness with enfortumab-based regimens and the availability of toripalimab in certain geographical areas.

Over the years, many biomarker-based therapies have been introduced into the solid tumor field. The traditional clinical research pathway has been to test novel therapies first in a refractory setting and then, gradually, move them to earlier lines. However, this strategy may hinder the development of promising compounds, as tumor evolution, clonal selection, and immune exhaustion reduce treatment effectiveness over time. Moreover, there is often reluctance to move novel therapies into the neoadjuvant setting because patients are potentially cured with standard-of-care strategies. Hence, many immune- and gene-targeted therapies remain applicable only in advanced/metastatic disease and often in the refractory setting, rather than in newly diagnosed disease. Yet, standard neoadjuvant therapies leave many patients at substantial risk for recurrence, and, furthermore, some types of surgery can be mutilating, and radiation and chemotherapy may be difficult to tolerate and may further attenuate chances of response to other agents in later lines of therapy. Although disease biology and competing standards of care must be considered in these scenarios, clinical trials offering precision biomarker-matched therapies earlier in the course of the disease should be an option for patients, with consent documents clearly outlining the risks, and that the chance of cure with standard radiation, chemotherapy, and/or surgery may be lost if the newer regimens are not effective. The emergence of ctDNA-based minimal residual disease detection also offers us the opportunity to identify cancer patients at high risk of recurrence before radiologic progression occurs, facilitating earlier intervention with biomarker-matched therapies.

The RC48-C016 trial¹ adds to the growing body of evidence that precision medicine can only reach its full potential when personalized targeted therapies are delivered promptly in earlier lines, potentially leading to deeper and more durable tumor responses. Timing is not the sole factor affecting the prognosis of cancer patients; optimal selection, dosing, and sequencing of targeted therapies are equally important; Even so, trials such as RC48-C016¹ strongly advocate for the early integration of biomarker-matched therapies in the management of patients with malignancies.

Author contributions

R.K. and A.S. conceptualized and drafted the initial version of the manuscript. R.K., A.W., and A.S. reviewed and edited the manuscript. “All authors have read and approved the article”.

Competing interests

The authors declare no competing interests.