Patients with clinical stage T2N1 or T3N0–1 rectal cancers who are eligible for sphincter-sparing surgery might be able to avoid preoperative radiotherapy if given induction FOLFOX prior to surgery.
Total neoadjuvant therapy for patients with locally advanced rectal cancer — whereby chemoradiotherapy and chemotherapy are administered prior to surgery — offers the potential for enhanced treatment tolerance and delivery, improvements in pathologic response at surgery, and nonoperative management for colostomy candidates who achieve a clinical complete response. However, for patients with high- or mid-rectal cancers undergoing total mesorectal excision, the role of neoadjuvant radiotherapy has been increasingly questioned.
To test the concept of avoiding neoadjuvant radiotherapy in this setting, investigators conducted a multicenter, noninferiority, randomized, phase 3 trial (PROSPECT) involving 1128 patients with clinical stage T2N1 or T3N0–1 high- or mid-rectal cancer who were candidates for sphincter-sparing surgery. Most patients were male, half had T3N1 cancers, 91% had T3N0–1 cancers, and 64% had cancers 5 to 10 cm from the anal verge. Half of patients received conventional neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy. The other half received induction chemotherapy with 6 cycles of FOLFOX, and those with a ≥20% reduction in the primary tumor proceeded to surgery without radiotherapy and received adjuvant chemotherapy.
At 5 years, disease-free survival was noninferior with induction FOLFOX versus chemoradiotherapy (80.8% vs. 78.6%; hazard ratio, 0.92, P=0.005), meeting the primary endpoint. Rates of local recurrence were similar with FOLFOX or chemoradiotherapy (1.8% and 1.6%, respectively), as were 5-year overall survival (89.5% and 90.2%) and pathologic complete response (21.9% and 24.3%). Nearly 90% of patients treated with FOLFOX avoided radiotherapy; 9.1% required neoadjuvant chemoradiotherapy after FOLFOX, and 1.4% required postoperative chemoradiotherapy. No new safety signals were observed.
Comment
The large, well-conducted trial indicates that the vast majority of patients with clinical stage T2N1 or T3N0–1 rectal cancers who are eligible for sphincter-sparing surgery can avoid the use of preoperative radiotherapy if given induction FOLFOX. This trial will change practice. The use of radiotherapy preoperatively will increasingly be relegated to more advanced rectal cancers or to patients requiring a permanent colostomy.
From 2008 to 2018, prevalence of adenomas changed from 12.4% to 14.1% among those younger than 50 years.
Colorectal cancer incidence per 100,000 changed from 9.1 in 1988 to 10.2 in 2018 among younger men.
Colorectal cancer incidence has increased since 1988 among men but not women younger than 50 years, suggesting that patient sex should be factored in when determining screening age, data from an Austrian study showed.
“CRC incidence and mortality decreased in the U.S. and many European countries over the last 30 years among adults aged 55 years and older, which could be an effect of higher adherence to CRC screening programs,”Daniela Penz, MD, of the Austrian Society of Gastroenterology and Hepatology, and colleagues wrote in JAMA Network Open. “At the same time, an increase in mortality and incidence rates among younger patients was noticed.”
Data derived from: Penz D, et al. JAMA Netw Open. 2023;doi:10.1001/jamanetworkopen.2023.34757.
They continued, “Despite the evidence of an increase in CRC incidence among younger adults, data about the prevalence of precursor lesions, such as adenomas, among younger individuals, especially those without symptoms, are still missing.”
Seeking to analyze the prevalence and number needed to screen (NNS) for adenomas, advanced adenomas and serrated lesions, as well as CRC incidence in individuals older than 20 years, researchers evaluated 296,170 patients (median age, 60 years; 50.9% women) who underwent screening colonoscopy within the Austrian quality assurance program between 2008 and 2018. They also analyzed CRC incidence using Statistic Austria data from 1988 to 2018. Of those included in the study, 11,103 (3.7%) were aged younger than 50 years.
Analysis showed 10.5% (NNS = 9) of individuals younger than 50 years and 21.9% (NNS = 5) aged 50 years and older had adenomas, while 3.9% (NNS = 26) and 6.9% (NNS = 15), respectively, had at least one advanced adenoma. Among patients aged 40 to 44 years, there was at least one adenoma present in 14.2% (NNS = 7) of men and 8.1% (NNS = 12) of women.
The prevalence of adenomas among men aged 45 to 49 years vs. 50 to 54 years was 17.1% (NNS = 6) vs. 20.2% (NNS= 5) compared with 10.2% (NNS = 10) vs. 12.4% (NNS = 8), respectively, among women.
From 2008 to 2018, prevalence of adenomas changed from 12.4% to 14.1% among those younger than 50 years and from 21.8% to 28.2% among those 50 years and older; change in advanced adenoma prevalence during the same time period was 4% to 5.2% and 7.3% to 6.8%, respectively.
For CRC, incidence per 100,000 individuals changed from 9.1 in 1988 to 10.2 in 2018 among men younger than 50 years (average annual percent change [AAPC] = 0.5%; 95% CI, 0.1-1) and from 9.7 to 7.7 among women of the same age (AAPC = –0.2%; 95% CI, –0.7 to 0.3). CRC incidence shifted from 217 to 143 (AAPC = –1.2%; 95% CI, –1.3 to –1.1) and 168 to 97 (AAPC = –1.8%; 95% CI, –1.9 to –1.6) among men and women, respectively, aged 50 years or older.
“This cohort study found that the prevalence of adenomas and advanced adenomas increased among younger adults in Austria,” Penz and colleagues concluded. “CRC incidence has increased since 1988 in males but not females younger than age 50 years.”
They continued: “These findings suggest that patient sex should be considered as a factor when determining the age for starting screening in further recommendations. Based on this study, screening should have started at age 40 years for males and age 50 years or even later, around age 55 years, for females.”
External-beam radiation therapy (RT) is standard of care (SOC) for pain relief of symptomatic bone metastases. We aimed to evaluate the efficacy of radiation to asymptomatic bone metastases in preventing skeletal-related events (SRE).
METHODS
In a multicenter randomized controlled trial, adult patients with widely metastatic solid tumor malignancies were stratified by histology and planned SOC (systemic therapy or observation) and randomly assigned in a 1:1 ratio to receive RT to asymptomatic high-risk bone metastases or SOC alone. The primary outcome of the trial was SRE. Secondary outcomes included hospitalizations for SRE and overall survival (OS).
RESULTS
A total of 78 patients with 122 high-risk bone metastases were enrolled between May 8, 2018, and August 9, 2021, at three institutions across an affiliated cancer network in the United States. Seventy-three patients were evaluable for the primary end point. The most common primary cancer types were lung (27%), breast (24%), and prostate (22%). At 1 year, SRE occurred in one of 62 bone metastases (1.6%) in the RT arm and 14 of 49 bone metastases (29%) in the SOC arm (P < .001). There were significantly fewer patients hospitalized for SRE in the RT arm compared with the SOC arm (0 v 4, P = .045). At a median follow-up of 2.5 years, OS was significantly longer in the RT arm (hazard ratio [HR], 0.49; 95% CI, 0.27 to 0.89; P = .018), which persisted on multivariable Cox regression analysis (HR, 0.46; 95% CI, 0.23 to 0.85; P = .01).
CONCLUSION
Radiation delivered prophylactically to asymptomatic, high-risk bone metastases reduced SRE and hospitalizations. We also observed an improvement in OS with prophylactic radiation, although a confirmatory phase III trial is warranted.
To determine if prophylactic radiation to asymptomatic high-risk bone metastases reduces the incidence of skeletal-related events (SRE), including pathologic fracture, spinal cord compression, orthopedic surgery to bone, and/or palliative radiation therapy for pain.
Knowledge Generated
In this multicenter randomized controlled trial conducted in the United States that included 78 adult patients with metastatic solid tumor malignancies, radiation reduced SRE at 1 year from 29% to 1.6% compared with standard of care. Additionally, overall survival was extended with use of radiation (median 1.7 v 1.0 years) with a hazard ratio 0.49, which maintained significance on adjusted analysis.
Relevance (B.G. Haffty)
This randomized phase II trial is relevant in demonstrating statistically and clinically significant decreases in SRE including pathological fracture, spinal cord compression, or orthopedic intervention with prophylactic radiation to asymptomatic but high risk bone metastasis.*
Black patients with cancer are significantly more likely to experience cardiotoxicity and congestive heart failure related to chemotherapy than White cancer patients are, a research review indicates.
“It’s important that both patients and clinicians be aware of these disparities so that more meaningful conversations around long-term cardiac health and cancer treatment can take place,” lead investigator Wondewossen Gebeyehu, with the University of Toronto, Canada, told theheart.org | Medscape Cardiology.
However, patients “should not avoid chemotherapy, as the most important thing is making sure they get the best cancer treatment possible, and studies already show Black patients may get less optimal cancer treatments,” Gebeyehu added in a statement.
Ana Barac, MD, PHD, chair, cardio-oncology, Inova Schar Cancer Institute and Inova Heart and Vascular Institute, Fairfax, Virginia, who wasn’t involved in the study, agrees.
“The most important message is to look at preexisting cardiovascular disease (CVD), oncology diagnosis, and be aware of existing disparities in a specific cancer and CVD,” Barac told theheart.org | Medscape Cardiology.
“What should NOT happen is to overinterpret this report of cardiotoxicity as an indication to modify/avoid planned cancer treatment to decrease cardiotoxicity. This approach could worsen oncology outcomes and lead to undertreatment of cancer, therefore posing real danger,” said Barac.
The study was presented April 14 at the American College of Cardiology (ACC) Advancing the Cardiovascular Care of the Oncology Patient 2023 conference.
Causes Unclear
Chemotherapy is known to increase the risk of cardiovascular heart failure and other forms of CVD, but less is known about racial disparities in the incidence of chemotherapy-induced cardiotoxicity.
Gebeyehu and colleagues conducted a systematic review and meta-analysis of the available literature to assess racial disparities in CV adverse effects among cancer patients who were treated with chemotherapeutic agents. They screened 7057 studies, fully reviewed 57, and included 24 studies, representing 683,749 participants, in their analysis.
Breast cancer was the most commonly reported malignancy. Other common malignancies were prostate, kidney, and hematologic malignancies such as leukemia and lymphoma.
Chemotherapeutic agents included anthracyclines (doxorubicin, daunorubicin), trastuzumab, and hormonal therapies.
Black race or African ancestry was associated with increased odds of chemotherapy-associated cardiotoxicity (unadjusted odds ratio [OR], 1.71; 95% CI, 1.40 – 2.10), as well as congestive heart failure (unadjusted OR, 1.92; 95% CI, 1.68 – 2.19).
Gebeyehu told theheart.org | Medscape Cardiology that it’s hard to speculate on causation with an analysis of preexisting data such as this. “Our initial analysis that we’ve reported on so far are unadjusted values, meaning they don’t adjust for those potential underlying factors,” he noted.
“However, some of the studies individually controlled for socioeconomic factors and still found increased vulnerability to chemotherapy-associated cardiotoxicity in patients of Black race or African ancestry,” Gebeyehu said.
“It’s certainly possible that a mix of both biological and socioeconomic factors are interacting to lead to these disparities. One example could be the underrepresentation of Black patients in clinical trials to develop drugs. These could lead to chemotherapeutic agents being poorly optimized in this population relative to other racial/ethnic groups,” he added.
Barac said this study adds to the growing body of evidence about the importance of racial disparities in CVD and cancer outcomes.
“It is important to note that only the unadjusted odds ratio was reported and that much more detail is needed to understand what may be underlying the disparities. It is critically important to await the adjusted analysis, as well as details of the type of cancers and treatment used, before clinical implications can be discussed,” said Barac, who served as co-director of the conference.
“The risk of cardiotoxicity needs to be presented in the context of the oncology and CV disease burden, as both can influence the risk, and there could be a synergistic effect of disparities,” Barac added.
Despite substantial advances in understanding of the molecular features of gliomas, the therapeutic options for these aggressive tumors remain scarce. Rich, Mitchell and colleagues provide their views about a phase 1 clinical trial testing the safety and efficacy of vaccines against cancer expressing mutant metabolic enzyme IDH1 in patients with high-grade glioma.
From the bench: Sameer Agnihotri and Jeremy N. Rich
Gliomas are the most prevalent primary brain tumors and remain incurable despite extensive molecular characterization and research aimed at identifying viable therapeutic vulnerabilities. Among the various glioma subtypes, diffuse gliomas and secondary glioblastomas are driven mostly by gain-of-function oncogenic mutations in genes encoding the metabolic enzymes IDH1 and, less frequently, IDH2, and thus are genetically distinct from primary glioblastomas1,2. Mutations in IDH1 are commonly found in heterozygosis and often result in the single-amino-acid substitution of arginine (R) with histidine (H) in the catalytic site of IDH1 at codon 132 (called ‘IDH1(R132H)’ here)1,2,3. Mutations in IDH1 and IDH2 result in neomorphic enzymatic activities that lead to production of the oncometabolite 2-HG4,5,6. 2-HG inhibits the enzymatic functions of many α-ketoglutarate-dependent enzymes, including histone and DNA demethlyases, and thus causes the aberrant epigenetic reprogramming seen in the CpG island methylator phenotypes7,8,9,10,11. The presence of mutations in IDH1 and/or IDH2 have led to intensive preclinical and clinical research aimed at developing clinical-grade inhibitors of mutant IDH1, some of which have achieved approval from the US Food and Drug Administration for certain indications, including acute myeloid leukemia or cholangiocarcinoma expressing mutant IDH1; however, despite promising preclinical evidence in support of the efficacy of these compounds, clinical studies of these mutant IDH1–targeted compounds for glioma have not yet progressed beyond early-phase clinical trials, mostly due to concerns about their ability to overcome the blood–brain barrier. This leaves few targeted therapeutic opportunities for patients with glioblastoma, and thus there is an urgent unmet need for the development of alternative strategies that could provide a suitable path for the treatment of these aggressive tumors.
Writing in Nature, Platten and colleagues now report the results of a phase 1 trial testing an anti-cancer vaccine designed to target neoantigens commonly found in patients with glioma bearing IDH1 mutations12 (Fig. 1). Their results provide proof-of-concept evidence of the feasibility and efficacy of this immunotherapy modality and open the path for the development of similar therapeutic approaches for the treatment of these lethal tumors.
Fig. 1: Summary of the NOA16 trial.
Anti-cancer vaccination typically consists of the administration of tumor-specific antigens that elicit adaptive anti-tumor immune responses. These antigens usually comprise ‘self’ peptides or ‘non-self’ peptides (such as cancer testis antigens or human papillomavirus proteins, respectively), although the best responses to anti-cancer vaccines are usually achieved when these are directed against antigens expressed exclusively by tumor cells. This has led to greater interest in the use of specific antigens that arise from endogenous tumor mutational processes and are generally known as ‘neoantigens’ or ‘neoepitopes’. Even though anti-cancer vaccines have been extensively explored in various settings with relative success, they have achieved uneven activity in neuro-oncology. More than 70% of diffuse gliomas harbor the IDH1 R132H mutation, an early genetic lesion expressed nearly uniformly by tumor cells, which renders this a potentially powerful therapeutic candidate. Additionally, this neoepitope is presented via the class II major histocompatibility complex (MHC)13 and thus represents an attractive potential target for immunotherapy.
Previous preclinical studies demonstrated that versions of an IDH1(R132H)-specific peptide vaccine (IDH1-vac) were capable of inducing sustained anti-tumor–specific therapeutic helper T cell responses in syngeneic MHC-humanized mice13. Platten and colleagues developed an array of peptides encompassing the R132H substitution within IDH1 and identified the peptide p123–142, which spans the codons 123–142 and includes the R132H substitution, as a potent inducer of specific anti-tumor immune responses to cells expressing mutant IDH1 (Fig. 1). On the basis of this promising preclinical evidence, Platten and colleagues designed a multi-center, phase 1 clinical trial (NOA-16; ClinicalTrials.gov identifier NCT02454634) to test the safety, feasibility and efficacy of a vaccine targeting mutant IDH1 in newly diagnosed patients with World Health Organization (WHO) grade III or grade IV glioma12 (Fig. 1).
In this proof-of-concept trial, Platten and colleagues demonstrated that the IDH1-targeting vaccine was safe and immunogenic and was capable of inducing both T cell and B cell immune responses across patients bearing a variety of human leukocyte antigen–encoding alleles. The authors established a mutation-specificity score to incorporate the duration and level of IDH1-vac-induced T cell immune responses and observed that patients with high scores showed predominant production of the cytokines TNF, IFN-γ and IL-17 by helper T cells, indicative of involvement of the TH1 and TH17 subtypes of helper T cells. The authors also followed up with the patients and assessed the 3-year progression-free and death-free rates, which were 0.63 and 0.84, respectively. Interestingly, treated patients displayed higher rates of pseudoprogression (PsPD), a condition in which patients develop mass lesions that resemble tumor growth by neuroimaging, than those of a molecularly matched cohort that had not been treated with the IDH1-targeting vaccine. PsPD indicates intratumoral inflammatory infiltration and reactions, with prior studies suggesting that patients who develop PsPD after conventional therapy may survive longer. PsPD after vaccination did not correlate with patient age, extent of resection, standard-of-care treatment, or tumor grade. Furthermore, PsPD did not correlate with specific copy-number variations, tumor-methylation class (e.g., the CpG island methylator phenotype), or deletion status for CDKN2A (which encodes a cyclin-dependent kinase inhibitor).
Overall, these results provide evidence that supports the proposal of the induction of specific anti-tumor immune responses after vaccination with a cancer-specific neoepitope.
From the clinic: Kailin Yang and Duane A. Mitchell
Of the 44 patients initially enrolled in the clinical trial, 32 met the inclusion criteria and received the vaccine; the authors were able to perform analysis on the safety and feasibility of this therapy on all the treated patients, including mid-term follow-up, and were also able to perform immunological profiling in a subset of 30 of these treated patients (Fig. 1).
In order to generate a comprehensive map of the complex immunological interactions taking place in the tumor microenvironment following administration of the neoantigen vaccine, the authors performed single-cell RNA sequencing of tumor samples from patients; this allowed them to delineate the heterogeneity of the immune-cell landscape, which eventually resulted in the identification of three distinct clusters of CD4+ T cells within PsPD masses, such as CXCL13+CD4+ T cells, which are key to sustaining anti-tumor immunity responses. Moreover, sequencing of T cell antigen receptors in patients with PsPD revealed that tumor-infiltrating helper T cell clusters displayed a predominance of a single T cell antigen receptor clone, which suggested that IDH1-vac induced the clonal expansion of mutant IDH1–specific helper T cells.
There are notable observations that arise at the interface of the clinical findings and immunological findings of this study that have substantial implications in support of further vaccine development for IDH1-mutant gliomas specifically and for glioma immunotherapy more generally. For example, the observation of vaccine-induced immune responses in more than 90% of the vaccinated participants spanning a broad repertoire of MHC-encoding alleles provides compelling proof-of-concept evidence of the induction of T cell immunity to a highly conserved and ubiquitously expressed glioma-specific mutant protein. Notably, the higher than expected frequency of PsPD in vaccinated participants (and, in a single case, tumor tissue after vaccination) demonstrates an increased frequency of mutant IDH1–specific T cells among tumor-infiltrating lymphocytes.
Despite the promising data in support of the proposal of mutant IDH1 neoepitope–reactive T cells that localize to the central nervous system, further confirmatory studies linking vaccine responses to radiographic and immunological changes are needed. Future prospective studies that incorporate specific imaging endpoints as well as systematic analyses of tumor tissues and/or cerebral spinal fluid will help answer important questions about the potential for imaging modalities to detect changes within gliomas after vaccination; the possibility of monitoring the activity of mutant IDH1–stimulated T cells through liquid biopsy of cerebrospinal fluid; and whether CD4+ T cells that recognize mutant IDH1 effectively elicit anti-tumor activity that translates into improved patient outcomes, or if other populations are involved and required in establishment of the long-term anti-tumor immune responses.
Among the limitations of the study, the trial was not sufficiently powered to determine the relationship between vaccination and patient outcomes, as expected from a phase 1 study; moreover, the overall survival and progression-free survival times for patients with IDH1-mutant gliomas would be expected to be prolonged within this subgroup of patients with glioma. The investigators observed a trend of higher mutation-specificity scores in patients with PsPD than in patients with progressive disease or stable disease, as well as indications of better vaccine-induced responses in patients with stable disease than in those with progressive disease. However, randomized and appropriately powered clinical trials will be needed to determine the long-term impact of this approach, and to discern whether specific immunological correlates can serve as biomarkers of clinical responses. The authors had previously demonstrated that patients have spontaneous T cell and antibody responses to mutant IDH1, and thus it would be very interesting to know whether baseline responses to the mutant protein influence vaccine responses, PsPD and clinical outcomes.
Although the results of this study are encouraging and provide a foundation for further development, some additional outstanding questions remain. For example, during follow-up, four of ten patients with methylation-class high-grade glioma experienced progressive disease. Moreover, PsPD was not detected in patients who did not respond to treatment. Although no molecular correlates were found in this study, it would be interesting to see if future studies can identify patients who will not respond or patients at greater risk of developing progressive disease. Future and larger clinical trials may additionally provide more-granular insights into the various subtypes and stages of this disease by looking at grade III gliomas and grade IV gliomas as distinct entities. As gliomas are highly heterogeneous and develop subclonal alterations during the course of the disease, this vaccine may also provide superior therapeutic indices in combination with other immunotherapy approaches, such as immune-checkpoint inhibition14. As 2-HG has been shown to impair T cell function, small-molecule inhibitors of mutant IDH1 may augment the anti-tumor efficacy of vaccines against mutant IDH115.
As mutant IDH1 is a clonal event, and its expression is detected almost universally in all tumor cells, the vaccine against IDH1 provides the basis of a potentially impactful therapeutic strategy. From a wider point of view, this study—along with the recent scientific advancements in vaccine technology—may provide the foundation for the exploration of vaccine-based therapies for other incurable cancers following a similar rationale, and the work by Platten and colleagues provides the proof-of-concept clinical evidence that will undoubtedly stimulate the development of similarly impactful therapeutic strategies.
Importance Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) account for 15% of all CRCs. Deficient MMR is a predictive biomarker associated with responsiveness to immune checkpoint inhibitors (ICIs) in solid tumors, including CRC. The remarkable effectiveness of ICIs in metastatic CRC has led to their evaluation in the neoadjuvant and adjuvant treatment of localized disease.
Observations Multiple prospective phase 2 studies in limited numbers of patients with localized dMMR CRC demonstrate high complete clinical and pathological response rates (60%-100%) to neoadjuvant ICIs, with low rates of grade 3 or higher ICI-related toxic effects. Given the median follow-up of 12 to 25 months in these studies, longer-term monitoring is needed to determine the durability of response and to ensure that oncologic outcomes are not compromised in patients undergoing nonoperative management. Neoadjuvant ICI therapy is especially attractive for patients with rectal cancer given the significant morbidity that accompanies pelvic irradiation and total mesorectal excision. Ongoing and planned prospective phase 2 trials will provide further data on important issues, including optimal neoadjuvant treatment duration, ICI monotherapy vs combination, and the need for adjuvant ICI therapy.
Conclusions and Relevance While this review found that early results of neoadjuvant immunotherapy for localized dMMR CRC show high rates of major and complete pathological response, longer-term follow-up data are needed to ensure that oncologic outcomes are not compromised and are ideally improved. Neoadjuvant ICI therapy in localized dMMR CRC represents a potential paradigm shift with implications for organ preservation.
Importance A series of high-profile clinical trials for patients with resectable early-stage non–small cell lung cancer (NSCLC) have recently changed the standard of care in this setting. Specifically, studies have demonstrated statistically and clinically significant improvements in efficacy with the targeted therapy for adjuvant osimertinib in patients with resected NSCLC harboring an epidermal growth factor receptor (EGFR) genomic abnormality (GA), whereas trials with chemotherapy combined with nivolumab in the neoadjuvant setting and others testing atezolizumab or pembrolizumab as adjuvant therapy have all demonstrated improvements in event-free survival (EFS) (for neoadjuvant therapy) or disease-free survival (DFS) (for adjuvant therapy). These trials introduce many open questions about how to apply these findings in clinical practice.
Observations Treatment with adjuvant osimertinib for 3 years was associated with significant improvement in both DFS and overall survival (OS), but the erosion of the DFS benefit after the duration of treatment ends suggests a potential value for more longitudinal treatment. The potential value of highly effective targeted therapies as adjuvant therapy for other GAs has a compelling rationale but no data at this time. Adjuvant atezolizumab or pembrolizumab, generally administered for 1 year after postoperative chemotherapy, are appropriate considerations, but only atezolizumab for patients with tumor programmed death-ligand 1 (PD-L1) levels of 50% has demonstrated a benefit in OS. Neoadjuvant chemotherapy with nivolumab offers a strong EFS benefit, a shorter interval of treatment, and radiographic and pathologic feedback for patients with resectable stage IB to IIIA NSCLC, although very recent randomized clinical trials of perioperative immunotherapy both combined with chemotherapy preoperatively and administered postoperatively highlight the debatable value of adjuvant immunotherapy after prior chemoimmunotherapy. Improved tumor shrinkage rates with neoadjuvant chemoimmunotherapy suggest the possibility that criteria for resectability may potentially be redefined in anticipation of a good response to neoadjuvant chemoimmunotherapy.
Conclusions and Relevance Developments in resectable NSCLC have arrived so rapidly that they have also created practical challenges of identifying optimal patients and prioritizing options among these new competing standards. In some cases, practical management requires clinical judgment and discussion with the patient to cover the gaps in prospective data. Caution should be exerted when extrapolating beyond the available data.
Question Can the combination of central nervous system (CNS) radiotherapy with pyrotinib and capecitabine improve CNS progression-free survival (PFS) in patients with ERBB2-positive breast cancer with brain metastases?
Findings In this phase 2 nonrandomized trial of 40 patients with ERBB2-positive breast cancer, the combination of CNS radiotherapy and pyrotinib plus capecitabine was associated with a 1-year CNS PFS rate of 74.9% and a median CNS PFS of 18.0 months, with an acceptable radiation necrosis rate.
Meaning The results of this trial suggest that there are potential benefits of combining radiotherapy with pyrotinib and capecitabine for patients with ERBB2-positive breast cancer with brain metastases, suggesting a promising novel treatment approach for this challenging clinical scenario.
Abstract
Importance The potential benefit of combining intracranial effective systemic therapy with radiotherapy for patients with breast cancer with brain metastases remains unclear.
Objective To assess the activity and safety of combining radiotherapy with pyrotinib and capecitabine in patients with ERBB2-positive breast cancer and brain metastases.
Design, Setting, and Participants This was a single-arm, single-center, phase 2 nonrandomized clinical trial with a safety run-in phase. Between January 2020 and August 2022, patients with ERBB2-positive breast cancer and brain metastases were enrolled. The data cutoff date was February 1, 2023.
Interventions Patients received either fractionated stereotactic radiotherapy or whole-brain radiotherapy. Treatment with pyrotinib (400 mg, once daily) and capecitabine (1000 mg/m2, twice daily, on days 1-14 of each 21-day cycle) was initiated from the first day of radiotherapy to the seventh day after the completion of radiotherapy and continued until disease progression or unacceptable toxic effects.
Main Outcomes and Measures The primary end point was 1-year central nervous system (CNS) progression-free survival (PFS) rate. Secondary end points included CNS objective response rate (ORR), PFS, overall survival (OS), safety, and changes in neurocognitive function.
Results A total of 40 female patients (median age, 50.5 years [IQR, 46-59 years]) were enrolled and received treatment, including 3 patients in safety run-in phase. With a median follow-up of 17.3 months (IQR, 10.3-26.9), the 1-year CNS PFS rate was 74.9% (95% CI, 61.9%-90.7%), and the median CNS PFS was 18.0 months (95% CI, 15.5 to not reached). The 1-year PFS rate was 66.9% (95% CI, 53.1%-84.2%), and the median PFS was 17.6 months (95% CI, 12.8-34.1). The CNS objective response rate was 85% (34 of 40). Median overall survival was not reached. The most common grade 3 or 4 treatment-related adverse event was diarrhea (7.5%). Asymptomatic radiation necrosis was identified in 4 of 67 lesions (6.0%) treated with fractionated stereotactic radiotherapy. Most patients maintained neurocognitive function, as evaluated by the Mini-Mental State Examination at different points.
Conclusions and Relevance The results of this trial suggest that radiotherapy combined with pyrotinib and capecitabine is associated with long intracranial survival benefit in patients with ERBB2-positive advanced breast cancer and brain metastases with an acceptable safety profile. This combination deserves further validation.
The optimal perioperative chemotherapy for patients with muscle-invasive bladder cancer is not defined. The VESPER (French Genito-Urinary Tumor Group and French Association of Urology V05) trial reported improved 3-year progression-free survival with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) versus gemcitabine and cisplatin (GC) in patients who received neoadjuvant therapy, but not in the overall perioperative setting. In this Article, we report on the secondary endpoints of overall survival and time to death due to bladder cancer at 5-year follow-up.
Methods
VESPER was an open-label, randomised, phase 3 trial done at 28 university hospitals or comprehensive cancer centres in France, in which adults (age ≤18 years and ≤80 years) with primary bladder cancer and histologically confirmed muscle-invasive urothelial carcinoma were randomly allocated (1:1; block size four) to treatment with dd-MVAC (every 2 weeks for a total of six cycles) or GC (every 3 weeks for a total of four cycles). Overall survival and time to death due to bladder cancer (presented as 5-year cumulative incidence of death due to bladder cancer) was analysed by intention to treat (ITT) in all randomly assigned patients. Overall survival was assessed by the Kaplan-Meier method with the treatment groups compared with log-rank test stratified for mode of administration of chemotherapy (neoadjuvant or adjuvant) and lymph node involvement. Time to death due to bladder cancer was analysed with an Aalen model for competing risks and a Fine and Gray regression model stratified for the same two covariates. Results were presented for the total perioperative population and for the neoadjuvant and adjuvant subgroups. The trial is registered with ClinicalTrials.gov, NCT01812369, and is complete.
Findings
From Feb 25, 2013, to March 1, 2018, 500 patients were randomly assigned, of whom 493 were included in the final ITT population (245 [50%] in the GC group and 248 [50%] in the dd-MVAC group; 408 [83%] male and 85 [17%] female). 437 (89%) patients received neoadjuvant chemotherapy. Median follow-up was 5·3 years (IQR 5·1–5·4); 190 deaths at the 5-year cutoff were reported. In the perioperative setting (total ITT population), we found no evidence of association of overall survival at 5 years with dd-MVAC treatment versus GC treatment (64% [95% CI 58–70] vs 56% [50–63], stratified hazard ratio [HRstrat] 0·79 [95% CI 0·59–1·05]). Time to death due to bladder cancer was increased in the dd-MVAC group compared with in the GC group (5-year cumulative incidence of death: 27% [95% CI 21–32] vs 40% [34–46], HRstrat 0·61 [95% CI 0·45–0·84]). In the neoadjuvant subgroup, overall survival at 5 years was improved in the dd-MVAC group versus the GC group (66% [95% CI 60–73] vs 57% [50–64], HR 0·71 [95% CI 0·52–0·97]), as was time to death due to bladder cancer (5-year cumulative incidence: 24% [18–30] vs 38% [32–45], HR 0·55 [0·39–0·78]). In the adjuvant subgroup, the results were not conclusive due to the small sample size. Bladder cancer progression was the cause of death for 157 (83%) of the 190 deaths; other causes of death included cardiovascular events (eight [4%] deaths), deaths related to chemotherapy toxicity (four [2%]), and secondary cancers (four [2%]).
Interpretation
Our results on overall survival at 5 years were in accordance with the primary endpoint analysis (3-year progression-free survival). We found no evidence of improved overall survival with dd-MVAC over GC in the perioperative setting, but the data support the use of six cycles of dd-MVAC over four cycles of GC in the neoadjuvant setting. These results should impact practice and future trials of immunotherapy in bladder cancer.
NRG Oncology Phase III clinical trial, NRG-GY018, evaluating pembrolizumab in combination with standard of care chemotherapy (carboplatin and paclitaxel) met its primary endpoint of progression free survival (PFS) for the treatment of patients with stage III-IV or recurrent endometrial carcinoma, regardless of mismatch repair status. A pre-specified interim analysis, conducted by an independent Data Monitoring Committee, demonstrates that pembrolizumab in combination with chemotherapy has a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone in both study cohorts, mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR). The full results of this trial will be presented at an upcoming scientific conference.
NRG-GY018, a randomized, blinded, placebo-controlled study, accrued 819 women with stage III-IV or recurrent endometrial cancer. Two independent cohorts were evaluated, patients with endometrial cancers that are dMMR and patients with endometrial cancers that are pMMR. Patients were randomly assigned to receive pembrolizumab combined with carboplatin and paclitaxel (for a planned six, 3-week cycles), followed by pembrolizumab maintenance (for up to fourteen, 6 week cycles) or placebo combined with carboplatin and paclitaxel, followed by placebo maintenance.
Patients with advanced stage or recurrent endometrial cancer, the most common type of gynecologic cancer in the U.S., face a poor prognosis with limited treatment options. This is particularly notable in patients who progress after prior platinum-based adjuvant therapy with disease not amenable to curative surgery or radiation. In this study, pembrolizumab in combination with carboplatin and paclitaxel resulted in a statistically significant and clinically meaningful improvement in PFS in both the dMMR and pMMR study populations. We look forward to presenting these exciting findings at an upcoming scientific congress.”
Ramez Eskander, MD, of the University of California San Diego Moores Cancer Center and the Principal Investigator of the NRG-GY018 trial
This project was supported by the NRG Oncology Operations grant U10CA180868 and the NRG Oncology SDMC grant U10CA180822 from the National Cancer Institute (NCI), part of the National Institutes of Health and conducted by the NCI National Clinical Trials Network. Funding and support were also received from Merck & Co., Inc. through a Cooperative Research and Developmental Agreement with NCI. NRG-GY018 was conducted with funding supplemental to the CRADA from Merck in an Agreement between Merck and The GOG Foundation d/b/a NRG Oncology Philadelphia East.
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