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Corresponding author. Address for correspondence: Roberto Ferrara MD, Medical Oncology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano.
Medical Oncology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, ItalyMolecular Immunology Unit, Department of Research Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
Since of the first approval of nivolumab in previously treated patients with NSCLC in 2015, the pipeline of anti–programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) agents in clinical and preclinical development has become more and more crowded. In the past seven years, five PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab, cemiplimab, and durvalumab) have been approved by the U.S. Food and Drug Administration (FDA) for NSCLC treatment, and five additional agents (camrelizumab, sintilimab, tislelizumab, toripalimab, sugemalimab) have granted approval by Chinese National Medical Product Administration on the basis of randomized clinical trials conducted in patients of Asian ethnicity. The me-too drug tsunami has rapidly overwhelmed medical oncologists and, in such a scenario, it has become extremely complicated for physicians to understand the novelty and the scientific rationale beyond each agent to make reasonable treatment choices.
Contrary to other anti–PD-1 me-too drugs, tislelizumab has been engineered to eliminate Fc-γ receptors (Fc-γRs) and complement-1q binding. The interaction of the anti–PD-1 antibody Fc and the Fc-γR has been previously described as a mechanism of hyperprogressive disease, an acceleration of tumor growth during treatment with anti–PD-1/PD-L1 agents reported in 14% to 26% of pretreated NSCLC and associated with poor survival.
Specifically, it has been postulated that the Fc-tail of anti–PD-1 antibody may bind to Fc- γR2b on macrophages, triggering an M2-polarization, which ultimately enhances immunosuppression—thus, cancer growth.
Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade.
In the RATIONALE-303 trial, tislelizumab improved overall survival compared with docetaxel both in all-comer pretreated patients with NSCLC and in patients with PD-L1 expression on tumor cells greater than or equal to 25%.
Tislelizumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer (RATIONALE-303): a phase 3, open label, randomized controlled trial.
Of note, early and durable separation of Kaplan-Meier overall survival curves was observed with no violation of the proportional hazard assumption and absence of additional deaths in the immunotherapy arm compared with the chemotherapy arm. This pattern strongly contrasts with what was reported by other trials with immune checkpoint inhibitors in this setting: in CheckMate-057,
as an example, a crossing of the survival curves occurred at 6 months with 14 early additional deaths observed in the first 3 months of treatment in the nivolumab arm compared with docetaxel. These results suggest that tislelizumab may have a potential role in preventing early mortality from Fc-γR macrophage-mediated hyperprogressive disease, especially in those tumors with high macrophage infiltration (Fig. 1). Macrophages have been reported to reduce the activity of anti–PD-1 agents by stealing and eliminating anti–PD-1 antibodies bound to T cells.
Therefore, being less sensitive to macrophage-mediated degradation, tislelizumab could also potentially maintain its activity in patients with liver metastases, which are usually characterized by a desert-immune environment because of T-cell killing by hepatic macrophages.
In addition, tislelizumab may have significant activity in other thoracic cancers, such as mesothelioma, in which macrophages have been reported to be abundant and impair T-cell infiltration and functions.
Aside from specific mechanisms of action, the identification of peculiar biomarkers for patient selection is of paramount significance in the me-too drug development. In RATIONALE-303, an exploratory biomarker analysis revealed a potential association of NOTCH 1-4 mutations and high tissue tumor mutational burden (TMB) with survival benefits on tislelizumab (Fig. 1). Although the identification of NOTCH gene alterations in NSCLC dates back two decades ago, the complex pattern of activating or inactivating mutations makes the understanding of their biological relevance still very incomplete. For example, NOTCH 1 mutations, occurring in 10% of NSCLC, are associated with gain of functions, whereas for the NOTCH 2 gene, both activating and inactivating alterations have been reported. In addition, opposing roles for NOTCH 1 and NOTCH 2 signaling have been described in a KRAS-mutated lung cancer mouse model.
These data argue the use of NOTCH 1 to 4 as a homogeneous and unique class of mutations with similar biological functions. Although NOTCH signaling is associated with lung cancer cell survival and progression, NOTCH activation has also been associated with an antitumor immune microenvironment characterized by increased infiltration with tumor-specific CD8+ T cells and enhanced M1 macrophage polarization.
The prognostic role of NOTCH mutations has been mainly evaluated in the context of KRAS-mutant NSCLC models, in which increased activity of the NOTCH signal correlated with higher tumor grade and resistance to chemotherapy and emerged as a potential targetable pathway.
STK11 and KEAP-1 mutations also usually co-occur with KRAS mutation, but contrary to what is reported for NOTCH mutations, they have been associated with an immune suppressive microenvironment and poor survival on anti–PD-1/PD-L1 agents, particularly in STK11, KEAP-1, and KRAS triple-mutant cases.
In RATIONALE-303, no information was provided regarding KRAS, STK11, or KEAP1 mutational status; therefore, whether the impact of NOTCH 1 to 4 mutations on survival on tislelizumab could be influenced by other co-mutations remains unclear. Aside from NOTCH 1 to 4 mutations, TMB on tissue samples has also been investigated as a biomarker for tislelizumab efficacy in an exploratory analysis encompassing 44% of the population. The authors reported that tislelizumab benefit increased with higher TMB and the greatest effect was observed for TMB greater than or equal to 14 mutations per megabase (mut/Mb). Consistent with these findings, a recent retrospective analysis of three independent cohorts including more than 1500 patients with NSCLC receiving PD-1/PD-L1 inhibitors, revealed that a very high TMB in the upper decile (corresponding to ∼20 mut/Mb by next-generation sequencing and 16 mut/Mb by whole exome sequencing) was associated with significantly improved response and survival compared with a lower TMB.
Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels.
Given that high mutated NOTCH signaling correlated with increased mutations in DNA damage response genes and high TMB in two cohorts of patients with NSCLC,
it is unclear what is the extent of overlap between these biomarkers of response in RATIONALE-303. Altogether these data suggest that in the future, a biomarker-driven strategy for the clinical development of anti–PD-1/PD-L1 me-too drugs should be highly recommended to guide clinicians’ treatment choices according to the biological peculiarities of each single agent.
Amidst the anti–PD-1/PD-L1 me-too drugs tsunami, consideration regarding the implications on health system sustainability and access to cancer treatments necessarily emerges. The new wave of Asia-based me-too drug development could be abundant, but not necessarily redundant. In fact, important knowledge generation in me-too clinical trials can derive from new data on activity and safety across diverse ethnical populations: me-too drugs with non–me-too outputs. In this regard, clinical trials have historically been poorly inclusive of non-White ethnical groups, resulting in a polarization of the evidence toward high-income and ethnically-defined populations and posing major challenges in the generalizability of the trial results at a global level.
whereas, in RATIONALE-303, 80% of patients were Chinese. The importance of ethnical diversity in immunotherapy clinical trials is based primarily on research needs because ethnicity-specific differences in the innate and adaptive immune response have been widely described and can have important implications for the safety and efficacy of immunotherapy drugs. As an example, in gastric cancer, a higher expression of effector T-cell markers and a lower expression of T-regulatory cells markers in non-Asian compared with Asian patients has been reported.
Reductio ad unum of the need to be inclusive in clinical trials to a biological question alone would jeopardize the complex dimensions of patients in the context of the social determinants of health—encompassing the broad spectrum of other factors such as the use of complementary medicines, diet, environmental exposures, and daily habits that can impact on cancer-related outcomes beyond biology per se. Recently, the U.S. FDA rejected the approval of the anti–PD-1 Chinese drug sintilimab, partly because the pivotal trial, ORIENT-11,
Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (Oncology pRogram by InnovENT anti-PD-1-11).
had included only Asian patients. Sintilimab’s manufacturer committed to bring the promises of me-too drug development for the first time, with a proposed disrupting reduction of the drug price up to 40% to 90% compared with the price of approved anti–PD(L)1 compound on the market. Although me-too drug development has been justified often as a way to enhance market competition, end monopolies, and reduce the costs of medicines, that is more a speculation than a real fact.
Actually, lower costs alone do not typically result in health system sustainability, and the question must be always contextualized as part of the national cancer-control goals to result in real population health benefits. As an example, a cross-sectional analysis of cancer medicines labeled as essential by oncologists revealed that although pembrolizumab was the most important cancer drug in high-income countries, it was not even listed in the top 20 drugs for low- and middle-income countries (LMICs), in which financial barriers existed also for older cytotoxic chemotherapies.
Therefore, immunotherapy indications that bring high therapeutic value might permeate the market of LMICs, whether companies commit to global health goals, catalyzing affordability and sustainability through fair pricing attitudes. The future of me-too immunotherapy drug development should pursue precision medicine approaches, expanding the representativeness of ethnically diverse patients, although keeping the promise to catalyze affordability and enhance access to drugs with high benefit for all patients (Fig. 1). Developing clinical trials that enroll in LMICs is not enough. It is time to frame clinical research within national health priorities, giving back to people access to medicines in terms of affordability, diversifying patient populations, and promoting coordinated worldwide regulatory efforts.
In conclusion, the next-generation millennials' me-too drugs in upcoming clinical trials should bet on novelty in mechanisms of action, biomarkers-based patient selection, affordability goals, and inclusion of different ethnicities to be one step ahead of the older baby boomers’ immunotherapies.
CRediT Authorship Contribution Statement
Roberto Ferrara: Conceptualization, Writing - original draft preparation, Visualization, Supervision, Writing - reviewi and editing.
Biagio Ricciuti: Conceptualization, Writing - original draft preparation, Writing - review and editing.
Chiara Ambrogio: Conceptualization, Writing - original draft preparation, Writing - review and editing.
Dario Trapani: Conceptualization, Writing - original draft preparation, Supervision, Writing - review and editing.
References
Ferrara R.
Mezquita L.
Texier M.
et al.
Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy.
Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade.
Tislelizumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer (RATIONALE-303): a phase 3, open label, randomized controlled trial.
Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels.
Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (Oncology pRogram by InnovENT anti-PD-1-11).
Disclosure: Dr. Ferrara reports receiving advisory board fees from Merck Sharp & Dohme and Beigene, and travel/accommodations fees from Daichii Sankyo not related to the present article. Dr. Ricciuti reports receiving consultant fees from Regeneron not related to the present article. Dr. Ambrogio reports receiving research fees from Revolution Medicines, Aelin Therapeutics, Verastem, Roche, and Boehringer Ingelheim not related to the present article. Dr. Trapani declares no conflict of interest.
The phase 3 RATIONALE-303 trial (NCT03358875) investigated the efficacy and safety of tislelizumab versus docetaxel in pretreated patients with advanced NSCLC. Here, we report the efficacy and safety results and describe the exploratory biomarker analyses.
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