successful abstracts. And I asked our fellow Dr. Wesley Burkett, originally from Alabama, then Oklahoma for residency, and he was gracious enough to present the update. So Wes is here, and he just probably passed his boards today, right, Wes? He took his treat. Dr. Burkett took his boards today, then came to give us a talk. I mean, this is an amazing fellow, huh? Yes, he is. If I passed my board today, I would be drunk tonight in celebration. I'm hoping he had dinner. So anyways, highlights of ESMO, right? Or IGCS? Was it IGCS or ESMO? I'm forgetting. A lot of these were presented at Summer, but it's IGCS. Oh, yeah, sorry. It was IGCS. My apologies. We're gonna do ESMO another time. Sorry about that. But a lot of them, they present some of these at ESMO as well. So they'll highlight some. My apologies. But all right, thank you, Dr. Van Lee. So I will get started. There's three different, if y'all can see my screen, correct? Yes, yes. Okay, perfect. And so I chose three different oral abstracts that were presented at the most recent meeting that I had found interesting. The first two we'll discuss is involving cervical cancer. The first is a phase three trial of SNF map versus chemotherapy and recurrent and metastatic cervical cancer. The next is the findings from the phase three Outback trial, which is also presented at ASCO in the spring. That will be discussed. And then finally, we will discuss an abstract associated with ovarian cancer and is looking at MIRV in combination with Bevacizumab in recurrent ovarian cancer. So the first oral abstract of the conference was the results of the phase three trial of SNF map versus investigator's choice, chemo and recurrent metastatic cervical cancer. So worldwide, cervical cancer is the fourth most common cancer and the fourth leading cause of cancer death in women and patients with recurrent or metastatic disease. Platinum based chemotherapy with or without Bevacizumab has a median survival between 13 to 18 months. And unfortunately, there is no survival benefit with second line systemic therapy. Recently, there has been interest in targeting the PD-L1 pathway as infection by HPV with genomic integration provides immunologic, excuse me, immunogenic foreign antigens that may amplify PD-L1 expression and playing a key role in immune escape of cervical cancer. So Smivap is a high affinity human hinge stabilized IgG4 monoclonal antibody to the PD-L1 receptor that is currently approved in metastatic in the US for metastatic squamous cell carcinoma of the skin, locally advanced in metastatic basal cell carcinoma, and for first line treatment of non small cell lung cancer in metastatic or locally advanced patients who aren't candidates for cervical resection, or definitive chemo or T. These tumors will also have to have a high PD-L1 expression. Phase one studies have demonstrated the activity in squamous cell carcinoma of the cervix with a safety profile that is similar to that of other PD-L1 inhibitors. So the objectives of the study was to investigate Smivap versus investigators choice chemotherapy and recurrent metastatic cervical cancer that has progressed after first line platinum based chemotherapy. 608 patients were enrolled, regardless of what their PD-L1 expression. 477 had squamous cell histology and 131 had adenocarcinoma. The stratification occurred by histology, geographic region, prior metastatic abuse, and ECOG performance status score. Patients were randomized to simepimab 350 milligrams every three weeks or investigators choice chemotherapy and were treated up to 96 weeks with options for retreatment. The primary endpoint was overall survival in the second, excuse me, at the second interim analysis. The independent data monitoring committee recommended the trial close early for efficacy based on a significant improvement in overall survival in treatment of squamous cell carcinoma by simepimab over the investigators choice chemotherapy. The data from that second interim analysis, what was presented during this oral abstract. So there were the patient demographics and baseline characteristics were well balanced between the arms. This is the data that led to the recommendation that the trial be stopped for early efficacy. The median overall survival for investigators choice chemo was 8.8 months versus 11.1 months with simepimab and squamous cell carcinoma patients. This is the survival analysis for the total population. The median overall survival for chemo is eight and a half months versus 12 months with simepimab. Survival of the adenocarcinoma population was consistent with the squamous cell carcinoma and overall population. The median overall survival for chemotherapy was seven months with 13.3 months with simepimab. For patient reported outcomes in the overall population, there was an increase in mean change from baseline in global health status, quality of life scale that was observed in favor of simepimab over investigators choice chemotherapy. Patients receiving simepimab generally improved or maintained global health scale quality of life from baseline while those on chemotherapy generally deteriorated. Of the 608 randomized patients, 254 had valid based on PD-L1 samples of which 126 received simepimab and 128 received the chemotherapy. Patients who were treated with simepimab with a PD-L1 expression of at least 1% showed an enhancement of survival benefit while those with PD-L1 expression less than 1% who were treated with simepimab had comparable survival to chemotherapy. Simepimab's duration of exposure was longer than that of chemotherapy at 15 weeks compared to 10 weeks. No new immune related adverse events were noted that were not had not been previously described for the PD-L1, excuse me, PD-1 inhibitor class. These adverse events occurred in about 16% in the simepimab arm. The safety profile of simepimab is consistent with previously reported safety data of simepimab as well as other PD-1 inhibitors. Adverse events that led to death occurred in 1.7% of patients in the simepimab arm compared to 0.7% in chemoarm, but none of the events that led to death were considered related to treatment with simepimab. So just to wrap up this abstract, this was the largest randomized study conducted to date in this population with simepimab being the first immunotherapy to demonstrate a statistically significant and critically meaningful survival benefit in recurrent and metastatic cervical cancer following progression after first-line platinum chemotherapy. The median overall survival in simepimab versus investigator's choice chemo was 11.1 months versus 8.8 months respectively in the squamous cell carcinoma population. Simepimab also demonstrated survival and overall response rate benefits in the overall and adenocarcinoma populations. And the numerical, numerical, numerical, let me say, oh, the overall, excuse me, the overall survival benefit for simepimab versus investigator's choice chemo was seen in patients with PD-AL1 less than 1%, although as expected, the benefit was larger in those patients who had PD-AL1 expression greater than equal to 1%. Changes in the global health quality of life favored simepimab in the overall population and the safety profile was consistent with what has been seen in other tumor types. There are a number of ongoing phase three trials looking at checkpoint inhibitors in combination for the first line treatment of cervical cancer, including Keynote 826, which was recently presented at ESMO and was published in the New England Journal of Medicine, which demonstrated the addition of Pembro to chemo with or without Bevlep to a 33% reduction in the risk of death and a 35% reduction in the risk of disease progression in death. Additionally, simepimab is actually undergoing priority review by the United States Food and Drug Administration currently with a target date of action of January 30, 2022. The next one is the OUTBEC trial. So locally advanced cervical cancer renders patients with the inability to undergo primary treatment with a radical hysterectomy with greater rates of metastasis and poor disease specific survival than disease confined to the cervix. Concurrent treatment with platinum and radiation has been the standard of care for locally advanced cervical cancer since 1999. The meta-analysis of N2008 reported this treatment and demonstrated an improvement in overall survival and disease free survival, but unfortunately treatment failures still occur and are often lethal as most deaths from cervical cancer are due to the development of metastatic disease. So the OUTBEC study was designed based on three phase three trials treating women with either locally advanced disease or high risk disease following radical hysterectomy, all of which had at least one dose of adjuvant chemo following treatment with chemo RT. RT of G9001 used one additional cycle of cisplatin and 5-FU following EBRT. GOG109 used two additional cycles of cisplatin and 5-FU following EBRT. And then the figure to the right arm A is patients who received two cycles of adjuvant cisplatin and gemcitabine. These studies when compared to historical control suggested superior outcomes compared to chemo RT alone. Therefore confirmatory trial was designed to study this OUTBEC chemotherapy. So this trial enrolled women with locally advanced cervical cancer with good performance status squamous adenocarcinoma and adenocarcinoma histology, adenosquamous carcinoma histology. And patients could not have periodic node involvement. Node positivity was determined by imaging. Patients were randomized to standard of care chemo RT or to chemo RT followed by a plan for cycles of adjuvant carboplatin and paclitaxel. The primary endpoint was overall survival. Chemo RT was given as cisplatin 40 milligrams per meter squared weekly during RT for which patients received 40 to 45 gray of external beam in 20 to 25 fractions plus brachytherapy. Adjuvant chemo was given as carboplatin with an AUC of 5 and paclitaxel 155 every three weeks for four cycles. The original protocol to this study was written for 780 patients planned for an 80% power and a two-sided alpha of 5% for an absolute improvement of 10% in overall survival at five years from 63% to 73% based on historical benchmarks with three years accrual and a median time to recurrence of 12 months. In 2016, this protocol was amended to 900 patients and was adjusted for absolute improvement of 8% in overall survival at five years from 72% to 80% to account for non-adherence with adjuvant chemo in the lower than expected event rate. The primary analysis was a direct comparison of survival rates at five years. Here are the demographics for the study. Unfortunately, the vast majority of enrollment was in white women while in the U.S. the incidence of cervical cancer is at least 30% higher in black women. So this is unlikely to be representative of the cervical population in the U.S. as well as the cervical cancer population globally. The baseline characteristics of disease were well balanced. The cohort was relatively high risk with approximately 50% of patients who enrolled had positive lymph node involvement. About 83% of patients completed all five assigned doses of cisplatin, but only 77% completed either four or five cycles of both cisplatin and radiation. When evaluating adherence with adjuvant chemotherapy, 22 patients who were assigned into the adjuvant therapy arm did not receive any adjuvant chemo and reasons for not starting adjuvant chemo in the adjuvant therapy group were doubled in women older than 60, doubled in non-Caucasian women, and not surprisingly tripled in those who did not complete chemo RT. As with what has been previously reported, the overall survival with a 60-month median follow-up shows no difference with use of adjuvant chemo versus standard chemo RT alone in the five-year overall survival around 70% is similar to that has been seen historically. Progression-free survival also showed no difference with a five-year progression-free survival that is similar to that of which has been seen. There were no significant differences in the outcomes in most subgroups that were evaluated. The only subgroup that did see a difference was in age, and in those that were 60 years and older, which only comprised 15% of the population, chemo RT seemed to do better than adjuvant chemotherapy, which is a bit odd, but again, it was such a small group. There's no difference in patterns of disease recurrence, even though about 50% of patients enrolled and had no positive disease, 67% and 73% of patients had no progression reported, and the local regional recurrence was 7% and 10%, and the remainder was distant, plus or minus local regional recurrence, which that was no different between the treatment arms, which the distant recurrence is what would have been expected to be improved with adjuvant chemo. Adverse events were as expected if you add carbaplatin and paclitaxel after chemo RT, but nothing out of range of expected. Beyond one year, the only difference between the arms was increased motor and sensory peripheral neuropathy, which was 7% versus 2% grade 2. So adjuvant chemotherapy does not appear to improve overall survival or progression-free survival in those women who are at high risk of treatment failure, and so for now, chemo RT remains the standard of care, but awaiting results of the Kala and Keynote studies. It is important that future research focus on adjuvant therapies that may be more tolerable and effective, as well as focusing on interventions to improve the completion rate of standard pelvic chemo RT. So the last one, a few slides on, is looking at the incorporation of PARP inhibitors and BEV, excuse me, this is with MIRV treatment in ovarian cancers, and so for the background of this, the incorporation of PARP inhibitors and BEV into maintenance therapy has resulted in an increase in the platinum-free interval, and thus leading to additional lines of platinum-based therapy and a higher occurrence of platinum hypersensitivity. Patients are living longer and are in need of additional therapies after treatment with platinum therapies is no longer an option. MIRV delivers the potent tubulin targeting mutansinoid DM4 directly to the tumor in patients expressing folate receptor alpha. MIRV has demonstrated significant activity in platinum-resistant ovarian cancer, both as a monotherapy and in combination with bevacizumab with an overall response rate of up to 56%. This trial compared or combined MIRV and bevacizumab to be used in a broader population of recurrent ovarian cancer, regardless of platinum status, with the primary objective being to assess the response-based anti-tumor activity of this combination in patients in which a non-platinum-based doublet would be appropriate with up to three prior treatments allowed. IHC scoring was performed for medium and high folate receptor alpha expression, and MIRV was given as a dose of six mg per kg, adjusted ideal body weight plus BEV every three weeks. The two-thirds of patients enrolled had received two or more prior therapies. 33 of 60 patients had high folate receptor alpha expression, and 40% had prior BEV use, and 35% had prior PARP use. About half of patients were platinum-resistant, and of those who were platinum-sensitive, the majority had a platinum-free interval of less than 12. It's a pretty high-risk group. There was an overall response rate of 64% in patients with tumors having a high folate receptor alpha expression, and in those with a high folate receptor alpha expression, treatment was highly active in those with platinum-resistance, and those with platinum-resist, platinum-sensitivity disease, with response rates of 59% and 69%, respectively. The response, the responses that were seen had a median duration of response for 9.7 months in the overall cohort, and at 11.8 months in those with high folate receptor alpha expression, and within those patients who had a high folate receptor alpha expression, the median duration of response was 9.4 months. In those patients with this high folate receptor alpha expression, 97% demonstrated tumor reduction in both platinum-sensitive and platinum-resistant disease, and were rapid and durable. Some of these patients had durable responses beyond 12 months, and some with responses lasting more than two years. Patients who had high folate receptor alpha tumors were found to have a more beneficial progression-free survival than treated with, or excuse me, when they were actually treated with the combination of MIRV and BEV with an overall median progression-free survival of 10.6 months, and a six-month progression-free survival of 80%, and a 12-month progression-free survival of 42%. In patients who had platinum-resistant disease that had the high folate receptor alpha tumors, the median progression-free survival was 9.7 months. Treatment-related adverse events were mostly low-grade and manageable. Grade 3 or 4 events were infrequent and with hypertension and neutropenia occurring with a frequency of more than 10% at 17% and 13% respectively. 30% of patients discontinued BEV and or MIRV due to treatment-related adverse events, and occurred after a median of 13 cycles of treatment. And so to conclude this abstract, the combination of MIRV plus BEV was highly active in a broad population of recurrent ovarian cancer patients with the high folate receptor alpha expression. These patients are in a population that are in need of more effective, well-tolerated, and non-platinum treatment options. The 64% overall response rate, 11.8 median duration, excuse me, 11.8-month median duration of response and 10.6 months median progression-free survival suggest hope in these patients with high folate receptor alpha expression regardless of what their platinum status is. In the growing platinum-sensitive population that are no longer candidates for platinum-based treatment, this study for which a majority had a platinum-free interval of less than a year demonstrated a 69% response rate with a 12.7-month median duration response and 13.3-month median progression-free survival. In those patients who had platinum-resistant disease, over half of whom had three prior lines of therapy, they had an overall response rate of 59% with a median duration of response of 9.4 months and a median progression-free survival of 9.7 months, which exceeds what was expected in this population. And so that was really fast for these three abstracts that had a lot of information, but to wrap up, just a quick summary on each one. The first abstract represented some FMAP may provide a new standard of care treatment option for patients with recurrent or metastatic cervical cancer after progressing on first-line platinum-based chemotherapy in a patient population that is associated with a poor prognosis. And then for the Outback trial for those with locally advanced cervical cancer, adjuvant chemotherapy should not be utilized after standard CISRT. Focus should be on how to improve the completion rate of ChemORT and following up the results of studies evaluating concurrent immunotherapies with ChemORT. And then finally, the combination of MIRV with BEV in patients with recurrent ovarian cancer has suggested beneficial outcomes in tumors with high-folate receptor alpha-expression, regardless of platinum status. Further development with MIRV and the combination of BEV is warranted. And so that is, I'll stop sharing, that is it. Thank you so much, Dr. Burkett.

Dr. Wesley Burkett

oral abstracts

SNFMAP

cervical cancer

chemotherapy

ovarian cancer