Introduction
In medical oncology, the deepening understanding of the mechanisms of cancer cell development has determined the appearance of a very large number of drugs involved in various mechanisms of cancer cell proliferation. Living in the age of evidence-based medicine, each new drug is first clinically validated following a complicated process of clinical trials. Phase III randomized studies that have positive results in terms of response rate, survival without signs of disease and overall survival are “pivotal studies” that lead to the introduction of the respective medication into current practice.
In general, the significant studies are presented by the international societies ESMO and ASCO, both online and during the congresses of these societies. This database, represented by the significant studies presented, must be the basis for the decisions to introduce new innovative drugs in each country. A proposal to identify the need to introduce an innovative medicine on the Romanian market would be the existence of a large committee of specialists who would know the incidence of neoplastic diseases in Romania, the international therapeutic schemes, and the results of the main studies published and analyzed by ESMO and ASCO. These specialists from the proposed commission must also face specialists in health economics, of course, in order to create a list of priorities for innovative medicines that take into account all realities. Of course, the creation and activity of such a commission require adequate funding.
In this context, I want to reproduce the analysis made by ESMO on some recent studies (ESMO News) which reveal the need to weigh the beneficial effects of an innovative medicine against the existing therapy at the given time, before taking the decision to introduce it to the market. Of course, in addition to scientific evidence, there can also be pressure from interested parties.
Evaluation of pemigatinib efficacy in FGFR-altered advanced solid tumors led to identification of new therapeutic areas for FGFR inhibition and drug failure mechanisms
In an exploratory phase II FIGHT-207 basket study, the investigators observed antitumor activity in cancers beyond cholangiocarcinoma and bladder cancer, as pemigatinib demonstrated also activity in patients with central nervous system tumors, pancreatic cancer (all KRAS wild-type), and cervical cancer. The findings suggest that FGFR inhibitors may be effective in cholangiocarcinoma with FGFR2 alterations other than fusions and rearrangements. Dedicated cohort for activating FGFR2 mutations allowed to explore the sensitivity of previously clinically unvalidated classes of mutations.
The study of potential mechanisms of primary resistance to pemigatinib revealed that baseline TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. Serial circulating tumor DNA (ctDNA) analysis revealed mechanisms of acquired resistance to pemigatinib in a variety of tumor types.
In conclusion, taking into consideration some deficiencies of the study that I don’t discuss now, the authors concluded: “However, the observations of response in this study are valuable as indicators for potentially actionable FGFR alterations and tumors that warrant deeper investigation”(1,2).
Trastuzumab deruxtecan shows antitumor activity and durable responses in heavily pretreated patients across multiple solid tumors with activating HER2 mutations
Primary results from the DESTINY-PanTumor01 study
In DESTINY-PanTumor01, the first tumor-agnostic study of a HER2-directed antibody drug conjugate conducted in patients with solid tumors harboring activating HER2 mutations, trastuzumab deruxtecan revealed encouraging and durable antitumor activity in heavily pretreated patients with limited treatment options, including those who had disease progression after previous HER2-directed therapy.
The study data provide clinical evidence for trastuzumab deruxtecan in heavily pretreated patients with solid tumors harboring HER2 mutations. Further research is warranted to better define which patients with different tumor histology subtypes and activating HER2 mutations will derive the most benefit from trastuzumab deruxtecan, according to Assoc. Prof. Bob T. Li of the Memorial Sloan Kettering Cancer Center in New York, USA, and colleagues, who published the findings on 3 May 2024 in The Lancet Oncology.
Overexpression of the HER2 protein or amplification of the HER2 gene has been observed as a target in various solid tumors, including breast, gastric, biliary tract, pancreatic, and endometrial cancers. Additionally, activating HER2 mutations might act as oncogenic drivers in various cancers. In a big analysis of multiple cancer types, 3.5% of all tumors had HER2 mutations. Most mutations occur in the kinase and extracellular domains (around 40% each) of the HER2 protein, and the prevalence of activating HER2 mutations varies by tumor type.
Limits of the study
Given the diverse patient population, further subgroup analyses are warranted to explore outcomes by HER2 mutation subtype, HER2 mutation domain, HER2 protein expression or amplification, and tumor type. However, this phase II study had a small sample size, particularly when considering the broad range of patient subgroups. The interpretation of outcomes by subgroup is therefore limited. Furthermore, the median duration of follow-up limits interpretation of the long-term safety and antitumor activity of trastuzumab deruxtecan from this study, and additional follow-up data would provide a more comprehensive understanding(3,4).
The growing role of AI in breast cancer (esmo.org)
The rapidly increasing integration of artificial intelligence (AI) into many aspects of breast cancer management calls for urgent definition of expected levels of evidence and bespoke regulatory and reimbursement processes.
Artificial intelligence is just about everywhere in the field of breast cancer right now. While AI research is only at an early stage in many cases, the pace of change is undeniable. Currently, the most solid evidence, and the biggest clinical application, is in the detection of breast cancer. Initial computer-aided detection systems, which have already been implemented in the augmentation of screening for some time, can now be outperformed by next-generation models. A key criticism of research in this area has been its reliance on retrospective data, but prospective studies are now beginning to emerge to confirm the AI’s benefits in supporting mammographic screening.
Other promising uses of AI in breast cancer are some way behind. In a related application – the prediction of future breast cancer risk to enable tailoring of more intensive screening for women at high risk –, AI models in combination with traditional risk models may prove to be a sensitive tool. A number of companies in several countries are already developing models, but few – if any – have received regulatory approval. AI has also driven a change in pathology diagnosis, from interpretation using a microscope to interpretation using a computer, meaning that virtual slides are now a must. In addition to aiding diagnosis, these virtual slides may offer other clues that will improve the patients’ management. For instance, the research on using AI to predict prognosis beyond classical markers is already quite advanced and it may provide a very easy, very rapid and very convenient alternative to expensive genomic tools to help guide treatment selection. The use of AI to guide radiotherapy, for example, predicting dose distribution, is also an evolving field(5).
Feasibility and safety of preoperative treatment with nivolumab and relatlimab in patients with resectable NSCLC stages IB, II and IIIA
With all randomized patients reaching the primary study endpoint, that is proceeding to surgery within 43 days of initiation of immune checkpoint inhibitor (ICI) therapy, NEOpredict-Lung confirms the feasibility in both study arms to receive two preoperative doses of nivolumab (anti-PD1) with or without relatlimab (anti-LAG3) antibody therapy. Achieving R0 resections in 95% of patients compares favorably with other studies of ICI-based neoadjuvant treatment in patients with non-small cell lung cancer (NSCLC), with operation rates mostly around 80%.
The safety of preoperative nivolumab plus relatlimab was supported with no apparent difference in overall frequency and severity of adverse events (AEs), treatment-related AEs and immune-related AEs compared with the reference nivolumab. Further exploration of dual targeting of PD1 and LAG3 in NSCLC is warranted, according to Doctors Martin Schuler of the University Hospital Essen in Essen, Germany, Kristof Cuppens of the Jessa Hospital in Hasselt, Belgium, and colleagues, who published the findings on 30 April 2024 in Nature Medicine.
In the setting of ICI therapy, reinvigoration of a suppressed immune response may be more effective while tumor infiltrating lymphocytes are still present in their native tumor context. Besides demonstrating safety and feasibility, the spectra of clinical and histopathological responses observed in studies with preoperative ICI therapy directed against PD1, PD-L1, CTLA4 and less-established targets in patients with resectable NSCLC, were correlated with exploratory biomarker analyses.
More recently, preoperative PD1/PD-L1 antibodies combined with platinum-based chemotherapy have been explored. Although this approach resulted in impressive histopathological response rates and improved event-free survival, combined chemoimmunotherapy may obscure the contribution of the ICI component at the single patient level. Across larger studies of preoperative chemoimmunotherapy, approximately 20% of patients failed to proceed to curatively intended surgery. Further, patients who might have been served perfectly well with ICI therapy alone were exposed to the additional toxicities of chemotherapy.
Based on distinct and potentially synergistic mode of action, combined targeting of the immune checkpoints LAG-3 and PD1 is a rational choice to overcome immune resistance in NSCLC. Both PD1 and LAG-3 are expressed by exhausted T cells. Dual blockade of both immune checkpoints synergistically enhanced T cell function and antitumor activity in preclinical models.
The study NEOpredict-Lung was designed to explore the feasibility and safety of preoperative dual targeting of PD1 and LAG-3 in patients with resectable NSCLC stages IB, II or IIIA. Secondary endpoints include the assessment of pathological and radiographic responses, survival endpoints and quality of surgical resections. Moreover, the study intends to leverage the neoadjuvant setting for exploratory analyses of specific biologies associated with response or resistance. Patients are randomly assigned to nivolumab plus relatlimab or nivolumab monotherapy, the latter serving as a reference for the evaluation of toxicity, clinical activity, and biological impact of dual targeting of PD1 and LAG-3 in resectable NSCLC.
In this ongoing, open-label phase II study, 60 biomarker-unselected, treatment-naive patients with resectable NSCLC were randomized to receive two preoperative doses of nivolumab with or without relatlimab. The primary study endpoint was the feasibility of surgery within 43 days, which was met by all patients. Curative resection was achieved in 95% of patients. Major pathological (defined as ≤10% viable tumor cells) and objective radiographic responses were achieved in 27% and 10% in the nivolumab group, and in 30% and 27% in the nivolumab plus relatlimab group of patients, respectively.
In 100% of patients in nivolumab group and in 90% in nivolumab plus relatlimab group of patients, tumors and lymph nodes were pathologically completely resected. With 12 months median duration of follow-up, the disease-free survival and overall survival rates at 12 months were 89% and 93% in the nivolumab group, and 93% and 100% in the nivolumab plus relatlimab group, respectively.
Both treatments were safe, with grade ≥3 treatment-emergent adverse events reported in 10% and 13% of patients per study arm. The exploratory analyses provided insights into biological processes triggered by preoperative immunotherapy.
This study establishes the feasibility and safety of dual targeting of PD1 and LAG-3 before lung cancer surgery. Based on early signals of clinical and biological activity obtained with this and another recently reported study in patients with metastatic NSCLC, further exploration of dual targeting of PD1 and LAG-3 in NSCLC is warranted. The authors wrote that negative correlation of histopathological response with the intratumoral representation of suppressive immune cell subsets is a key finding of their study. Another key observation of NEOpredict-Lung is how rapidly ICI-induced immune activation may shape the individual genomic landscapes of NSCLC.
Overall, the study findings suggest that in a subgroup of patients nivolumab with or without relatlimab failed to reinvigorate an immune response that significantly impacts on clonally diverse tumors. In another subgroup, four weeks of nivolumab with or without relatlimab were sufficient to empower complete immune eradication of lung cancers, which precluded meaningful longitudinal genomic analyses. In a third subgroup of patients who achieved substantial, but not complete histopathological responses, the enrichment of apparently resistant clones and depletion of sensitive clones were observed under the selective pressure mounted during preoperative ICI therapy. The latter hypothesis is corroborated by selected cases in which emergence of biologically plausible genomic resistance mechanisms, such as copy number gain of MYC and KRAS, and pathogenic variants of IDH1 and STK11, is observed by longitudinal genome sequencing.
The study management and translational research were performed at the University Medicine Essen, Jessa Hospital, and Antoni van Leeuwenhoek Hospital(6,7).
Consistent efficacy benefit with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive mBC with and without brain metastases
In an exploratory analysis of the DESTINY-Breast03 study, consistent systemic disease control and efficacy benefit were observed with trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer (mBC) with or without brain metastases. Median progression-free survival (PFS) was numerically longer with T-DXd than with T-DM1 for patients with brain metastases (15 versus 3 months), and it was estimated to be numerically longer for patients without brain metastases (not reached [NR] versus 7.1 months). A higher proportion of patients randomly assigned to T-DXd exhibited confirmed systemic objective response relative to those randomly assigned to T-DM1, including in patients with baseline brain metastases.
T-DXd treatment was associated with substantial intracranial response (65.7% versus 34.3% patients) and with reduction in CNS disease. Intracranial progression disease (PD) was observed in fewer patients randomized to T-DXd compared with T-DM1 (0% versus 20% of patients). For patients with brain metastases at baseline, those randomized to T-DXd experienced fewer PD events versus T-DM1 (48.8% versus 69.2%), according to Dr. Sara A. Hurvitz of the Division of Hematology and Oncology, Fred Hutchinson Cancer Center in Seattle, WA, USA, and colleagues, who published the findings on 24 April 2024 in the ESMO Open.
Several anti-HER2 therapies have been investigated for the treatment of brain metastases in patients with HER2-positive mBC. Before DESTINY-Breast03, T-DM1 was the standard-of-care treatment for patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane. T-DXd has previously demonstrated systemic efficacy in patients with brain metastases in a subgroup analysis of DESTINYBreast01. Intracranial efficacy of T-DXd has also been reported in both preclinical and clinical studies.
In the phase III DESTINY-Breast03 study, T-DXd demonstrated a clinically meaningful and statistically significant improvement in PFS versus T-DM1 in patients with HER2-positive mBC: NR (95% confidence interval [CI]; 18.5 months – not estimable [NE]) versus 6.8 months (95% CI; 5.6-8.2 months); hazard ratio (HR) 0.284 (95% CI 0.217-0.373; p<0.0001). The 12-month PFS was 75.8% for T-DXd (95% CI; 69.8% to 80.7%) versus 34.1% (95% CI; 27.7% to 40.5%) for T-DM1.
Based on the strength of DESTINY-Breast03 efficacy and safety data, the US Food and Drug Administration approved T-DXd for the treatment of patients with unresectable or advanced HER2-positive breast cancer who have received prior anti-HER2 therapy in the metastatic setting or in the adjuvant/neoadjuvant setting and have progressed within six months. In the latest article published in the ESMO Open, the study investigators report subgroup analyses for patients from DESTINY-Breast03 with and without brain metastases at baseline.
DESTINY-Breast03 is a randomized, multicentre, open-label, phase III study. The patients were randomly assigned 1:1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic brain metastases were eligible. Lesions were measured as per modified RECIST v1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR.
As of 21 May 2021, 43 of 261 patients randomized to T-DXd and 39 of 263 patients randomized to T-DM1 had brain metastases at baseline, as per investigator assessment. Among patients with baseline brain metastases, 20 of 43 in the T-DXd arm and 19 of 39 in the T-DM1 arm had not received prior local treatment for brain metastases.
For patients with brain metastases, median PFS was 15 months (95% CI; 12.5-22.2 months) for T-DXd versus 3 months (95% CI; 2.8-5.8 months) for T-DM1; HR 0.25 (95% CI; 0.13-0.45). For patients without brain metastases, median PFS was NR (95% CI 22.4 months – NE) for T-DXd versus 7.1 months (95% CI; 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI; 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1, and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with or without brain metastases, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1.
The authors concluded that this exploratory analysis shows that T-DXd provides meaningful efficacy benefit for patients with HER2-positive mBC either with or without clinically inactive/asymptomatic brain metastases in the second-line setting. These findings also further support the continued investigation of T-DXd in patients with brain metastases, including active brain metastases, a population for whom treatment options are currently limited.
In an accompanied editorial article, Doctors Sarah Sammons and Nancy U. Lin of the Dana-Farber Cancer Institute, Dana-Farber Brigham Cancer Center, and Harvard Medical School in Boston, MA, USA, wrote that T-DXd and tucatinib/capecitabine/trastuzumab are both excellent options for patients with brain metastases. They favor T-DXd in the second line for patients with extracranial progression who have stable brain metastases with low brain metastasis velocity, or those with small asymptomatic/untreated lesions. They prefer tucatinib/capecitabine/trastuzumab for patients with previously treated, but progressive lesions and in those with high brain metastasis velocity due to a paucity of data for T-DXd in this population relative to the much larger published experience with tucatinib to date. However, they would favor T-DXd over other systemic options in patients who have progressed on a tucatinib-based regimen.
The editorialists underlined that exploratory analysis of the DESTINY-Breast03 study suggests that T-DXd is the premier antibody drug conjugate for the treatment of patients with HER2-positive breast cancer brain metastases. The analysis underscores the pressing need to investigate T-DXd in patients with HER2-low expressing brain metastases, active HER2-positive brain metastases across other solid tumors, and leptomeningeal disease as the next crucial steps, as well as a move towards default inclusion of patients with brain metastases into clinical trials of antibody drug conjugates across the board.
This study was sponsored and designed by Daiichi Sankyo in collaboration with AstraZeneca(8-10).
Conflict of interest: none declared.
Financial support: none declared.
This work is permanently accessible online free of charge and published under the CC-BY licence.
