ABSTRACT
Background: Residual disease (RD) following neoadjuvant chemotherapy (NAC) in early HER2- negative breast cancer (BC) remains an unmet medical need. However, no therapies to date have tested their activity directly in chemo-resistant RD. Here, we hypothesized that combining an oncolytic virus such as T-VEC with atezolizumab may offer clinical benefit in patients (pts) with RD after standard NAC. To our knowledge, PROMETEO is the first trial that examines the activity of immunotherapy in pts with RD prior to surgery. Method(s): PROMETEO (NCT03802604) is a singlearm, open-label, multicenter phase II trial. Women with triple-negative BC (TNBC) or hormone receptor-positive/HER2-negative (HR+/HER2-) BC with baseline (i.e., before NAC) ki67 >= 20% were eligible. RD was confirmed with a magnetic resonance imaging (MRI) showing a tumor diameter >= 10 mm and a core-biopsy detecting the presence of invasive cells. Before surgery, T-VEC was administered intratumorally on week 1 (106 pfu/mL), then in week 4 and every 2 weeks thereafter (108 pfu/mL) for 4 injections. Atezolizumab (840 mg) was administered intravenously every 2 weeks for 4 infusions, starting at week 4. Surgery was performed in < 3 weeks after completing the treatment. The primary objective was to evaluate the efficacy of the combination, measured by the rate of residual cancer burden (RCB) class 0/1 at surgery. Tumor samples collected at 5 timepoints (before NAC, during screening period, after first dose of T-VEC, after first dose of T-VEC and atezolizumab and at surgery) were mandatory to assess gene expression, tumor-infiltrating lymphocytes (TILs), immune cells PD-L1 IHC (SP142), tumor mutational burden (TMB) by FoundationOne and other translational endpoints. Result(s): Between Dec 2018 to Feb 2022, 28 pts were enrolled: 20 pts with HR+/HER2- disease and 8 pts with TNBC. Median age was 47 (range 31-71) and 71% of pts were premenopausal. At diagnosis before NAC, clinical stage II disease represented 60.7%, cN+ 60.7%, median Ki-67 was 37.5% (range 20%-95%), high TILs (>=10%) 37%, median TMB was 3 (0-19) and only 1 of 27 pts (3.7%) had a PD-L1-positive tumor. After NAC, mean tumor size by MRI was 28.3 mm (10-93). Two pts discontinued from the trial (1 withdrawal of consent and 1 COVID infection). The completion of 5 cycles of treatment was achieved by 73% of pts. The overall RCB-0/1 rate was 25% (7 of 28, 95% IC 10.7 - 44.9%), all with RCB 0 (pathologic complete response [pCR]). The pCR rate was 30% in HR+/HER2- disease and 12.5 % in TNBC. Radiological response by MRI was achieved by 3 of 28 pts (10.7%). Interestingly, none of the 7 pts with a pCR had radiological response (stable disease n=5, progressive disease [PD] n=2). Six pts (21.4%) had radiological PD and had RCB 2/3. Overall, 27 (96%) patients had at least one treatment-emergent adverse event (TEAE) of any grade. Most common grade 1 or 2 AEs were fever (11 pts, 39.3%), ALT increased (9 pts, 32.1%), AST increased (8 pts, 28.6%), arthralgia (6 pts, 21.4%) and anemia (6 pts, 21.4%). Grade 3 reversible neutropenia occurred in 1 patient. Across all pts, significant increases (p< 0.001) in TILs, immune genes and immune PDL1+ cells were observed after 1 dose of TVEC, 1 dose of the combination and at surgery. Intrinsic subtype changes at surgery occurred in 73.1% of cases, mostly (46.1%) Luminal A/B converting to Normal-like. At surgery, 19 of 26 (73.1%) of tumors were PDL1+. Conclusion(s): Two months of T-VEC in combination with atezolizumab induced a pCR in a subgroup of pts with chemoresistant HER2- breast cancer. This effect is probably related to the immune activation provoked by the combined treatment. Interestingly, a high discrepancy was observed between the presurgical radiological imaging and the actual surgical pathological report. Pre-operative window-ofopportunity trials in this context might provide important clues regarding the activity of novel treatment strategies.
ABSTRACT
INTRODUCTION: The COVID-19 pandemic has disrupted many aspects of clinical practice in oncology, particularly regarding early cancer diagnosis, sparking public health concerns that possible delays could increase the proportion of patients diagnosed at advanced stages. In 2009, a cancer fast-track program (CFP) was implemented at the Clinico-Malvarrosa Health Department in Valencia, Spain with the aim of shortening waiting times between suspected cancer symptoms, diagnosis and therapy initiation. OBJECTIVES: The study aimed to explore the effects of the COVID-19 pandemic on our cancer diagnosis fast-track program. METHODS: The program workflow (patients included and time periods) was analysed from the beginning of the state of alarm on March 16th, 2020 until March 15th, 2021. Data was compared with data from the same period of time from the year before (2019). RESULTS: During the pandemic year, 975 suspected cancer cases were submitted to the CFP. The number of submissions only decreased during times of highest COVID-19 incidence and stricter lockdown, and overall, referrals were slightly higher than in the previous 2 years. Cancer diagnosis was confirmed in 197 (24.1%) cases, among which 33% were urological, 23% breast, 16% gastrointestinal and 9% lung cancer. The median time from referral to specialist appointment was 13 days and diagnosis was reached at a median of 18 days. In confirmed cancer cases, treatment was started at around 30 days from time of diagnosis. In total, 61% of cancer disease was detected at early stage, 20% at locally advanced stage, and 19% at advanced stage, displaying time frames and case proportions similar to pre-pandemic years. CONCLUSIONS: Our program has been able to maintain normal flow and efficacy despite the challenges of the current pandemic, and has proven a reliable tool to help primary care physicians referring suspected cancer patients.
Subject(s)
COVID-19 , Lung Neoplasms , Humans , COVID-19/epidemiology , Pandemics , Communicable Disease Control , Referral and Consultation , Lung Neoplasms/diagnosisABSTRACT
Background: The COVID-19 pandemic has disrupted many aspects of clinical practice in oncology, particularly in making timely cancer diagnosis. Our public health system has been concerned about potential delays leading to a higher proportion of patients with advanced stages. Our cancer diagnosis fast-track program (CFP) in the Clinic-Malvarrosa Health department in Valencia (Spain) is connecting primary care (PC) with different specialists to speed cancer diagnosis and treatment upon well founded suspicion. A 10-year evaluation of our CFP has recently been published. The aim of this analysis was to investigate the impact of the COVID-19 pandemic on the CFP. Methods: We analysed the programme flow during the state of emergency starting on March 16, 2020 for one year. Results: During that year, 975 suspected cancer cases were submitted to the CFP. The submissions only decreased during the times of highest COVID-19 incidence and stricter lockdown (March, April and October 2020). However, referrals were slightly higher than in the two previous years (average 877). Of those 975 patients, 817 were seen by the corresponding specialist. A cancer diagnosis was confirmed in 197 (24.1%) with 33% urological, 23% breast, 16% gastrointestinal and 9% lung cancer. Median time from referral to the specialist visit was 13 (interquartile range, 8 to 22 days) days and a diagnosis was reached in a median of 18 days (interquartile range, 10 to 30 days). In cancer patients, treatment was started in around 30 days (interquartile range, 13.5 to 51 days) from the time of diagnosis. Sixty-one percent of cancers were found in an early stage, 20% in a locally advanced stage, and 19% in an advanced stage. These intervals and proportions were similar to the previous years. Conclusions: Our programme has proven to be a reliable tool to help PC physicians referring patients with cancer suspicion cancer, maintaining its normal flow and efficacy despite the current pandemic. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.