Bob Kronemyer

“Checkpoint inhibitors (CPIs) have demonstrated strong activity in several tumor types; however, patients develop resistance,” said lead investigator Valentina Boni, MD, PhD, an oncologist at the Clara Campal Comprehensive Cancer Center in Madrid, Spain. “Also, for some tumor types like ovarian cancer, the activity of anti-programmed death-1 (PD-1) and anti-PD-1 ligand 1 (PD-L1) monotherapy is limited.”

Boni said there is an unmet medical need to improve the therapeutic landscape and enhance several combinations of immunotherapies for advanced solid tumors, including using nemvaleukin, an interleukin-2 (IL-2) cytokine.

ARTISTRY-1 is an ongoing phase 1/2 global study, with sites in North America, Asia Pacific and the European Union.

Patients were divided into 3 groups. Part A was intravenous nemvaleukin monotherapy daily for 5 days followed by 9 days off, then daily for 5 days followed by 16 days off for subsequent cycles, with a dose escalation starting at 0.1 µg/kg that progressed to 14 µg/kg. Of the 43 patients, the median age was 61 years and 60% were male.

“The majority were refractory patients with progressive disease and with very limited treatment options,” Boni told 

. “Common tumor types included melanoma, renal cell carcinoma (RCC), prostate cancer, colon cancer, and uterine cancer.”

Part B also was intravenous nemvaleukin monotherapy using the same dosing schedule as Part A, with the recommended phase 2 dose of 6 µg/kg.

The group comprised 37 patients with melanoma and 25 patients with RCC, with a median age of 66 years. There were an equal number of men and women with melanoma versus about 90% male for RCC.

The 100 evaluable patients in Part C received nemvaleukin, either 3 µg/kg or 6 µg/kg, every 21 days in combination with pembrolizumab, which was administered on day 1 only at a dose of 200 mg.

The median age of patients in the group was 60 years, with an equal number of men and women. Among the tumor types were ovarian cancer, triple-negative breast cancer (TNBC), cervical cancer, and breast cancer.

The study, which presented safety and antitumor activity data as of March 19, 2021, found that adverse events were in general transient and easily manageable among all 3 groups of patients, who had been on nemvaleukin treatment for up to 72 weeks.

“We have also seen preliminary activity in a broad spectrum of tumor types, including tumor types not approved or typically responsive to checkpoint inhibitors (CPIs) and in patients pretreated with CPIs,” Boni said. “Furthermore, we have observed responses in platinum-resistant-ovarian cancer, a very difficult to treat cancer with limited treatment options.”

For patients who received combination therapy, 19 objective responses were observed. An additional 3 patients had stable disease for at least 6 months: 1 with hepatocellular carcinoma, 1 with ovarian cancer and 1 with NSCLC.

Combination immunotherapy with anti-PD-1 plus anti-CTLA-4 antibodies – for example, nivolumab plus ipilimumab -- improves outcomes of women with recurrent or persistent ovarian cancer, compared with anti PD-1 alone (nivolumab), according to Boni. “However, this combination has been associated with an increase in severe toxicities,” she said.

Still, the current study concludes that nemvaleukin in combination with pembrolizumab has a similar rate of serious adverse events as nemvaleukin monotherapy.

“Overall, the study data are very encouraging to me,” Boni said.

Boni reports no relevant financial disclosures.

Boni V. ARTISTRY-1, a Phase 1/2 study evaluating nemvaleukin administered intravenously as a monotherapy and in combination with pembrolizumab. Data presented at: American Society of Clinical Oncology Annual Meeting; June 4-8, 2021. Virtual. Accessed June 8, 2021.

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Nemvaleukin alfa (Alkermes) was mostly well tolerated and indicated antitumor activity as both monotherapy and in combination with pembrolizumab among patients with advanced solid tumors, according to study results presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held virtually from June 4-8.

Nemvaleukin monotherapy and with pembrolizumab for ovarian cancer

 found that higher estradiol and follicle-stimulating hormone (FSH) levels, vasomotor symptoms and higher level of alcohol consumption were significant indicators of approaching natural menopause.

“We pursued this research topic because the accurate prediction of ANM could have many clinical implications and great significance in health promotion among postmenopausal women,” said principal investigator Eija Laakkonen, PhD, an Academy of Finland Research Fellow in aging and physiology at the Gerontology Research Center and Faculty of Sport and Health Sciences, University of Jyväskylä, in Finland.

 that for premenopausal women, “the accurate prediction of approaching menopause could be highly beneficial when making decisions about family planning and treatments for menopausal symptoms. Furthermore, ANM has been linked to cardiovascular disease, depression, osteoporosis and various cancers.”

Study participants were from the Estrogenic Regulation of Muscle Apoptosis (ERMA) study.

The investigators constructed 2 different easy-to-access ANM predictor models: a set of 32 non-self-reported covariates (including estradiol and FSH levels; menstrual cycle length) and a subset of 16 self-reported covariates (including smoking, education, and hormonal contraception).

“For the most part, the model predictors and their respective associations with ANM were in agreement with the literature,” Laakkonen said. “Thus, they will not come as a surprise to clinicians.”

However, some contradictory results were observed. “One interesting finding was that participants tended to increase their alcohol consumption when approaching menopause,” he said. “In fact, higher alcohol consumption was a significant predictor of the approaching menopause in our models.”

Conversely, smoking has been associated with an earlier age of menopause in several previous studies, “but we did not observe such association in our study,” Laakkonen said.

Because the study found a connection between lifestyle factors and the age at natural menopause, “clinicians can use this information to increase women’s awareness of the importance of a healthy lifestyle,” Laakkonen said. “But more studies on the subject are required for drawing conclusions about the causal relations.”

The authors noted that by gauging ANM, clinicians benefit in decision-making for use of contraception and treatments for menopausal symptoms in perimenopausal women.

Although the data set in the study was comprehensive and included vast numbers of candidate predictors that have been previously associated with ANM or are otherwise shown to fluctuate during the menopausal, “our data lacked some potentially strong predictors of the menopause, such as anti-Müllerian hormone levels, follicle counts and mother’s age at natural menopause,” Laakkonen said. “The impact of including these variables to the models would be worth investigating.”

Moreover, future studies using a similar methodological approach with a more comprehensive set of predictors and longer follow-up time “could lead to better predictive performance and enable the accurate prediction of ANM for women in their 30s or early 40s,” Laakkonen said.

The investigators also constructed a model using only easily accessible variables, “which clinicians can obtain by merely interviewing patients without any laboratory measurements,” Laakkonen said. “It is intriguing to envision developing this type of a model to a future online tool for clinicians and women themselves to estimate ANM.”

Laakkonen reports no relevant financial disclosures.

Hyvärinen M, Karvanen J, Aukee P, et al. Predicting the age at natural menopause in middle-aged women. 

Besides sex hormone levels, predictors for the age at natural menopause (ANM) include irregularity of menstrual cycle, menopausal symptoms, life habits and socioeconomic factors, according to a retrospective study of 105 middle-aged women who kept bleeding diaries.

Predicting the age at natural menopause

In cases of perineal cyclical pain, with or without previous perineal damage, clinicians should consider perineal endometriosis, according to findings from a systematic review of diagnosing and treating vulvo-perineal endometriosis published in the journal 

Diagnosis via clinical exam, perineal ultrasound, and pelvic MRI is advised.

The authors searched Cochrane Library, Medline/PubMed, Embase, and ClinicalTrials.gov for papers in English, Spanish, Portuguese, French, or Italian from inception to July 2020.

The authors noted that vulvo-perineal endometriosis is an exceedingly rare entity, with only approximately 300 cases reported in the literature since 1923. The 90 included studies comprised 283 patients, with a mean age of 32.7 years.

Overall, 95.3% of patients presenting with vulvo-perineal endometriosis had undergone episiotomy, perineal trauma, vaginal injury, or surgery. Only 4.7% of patients developed vulvo-vaginal endometriosis spontaneously, ie, without any apparent condition favoring it.

Nearly all patients (98.2%) sought medical advice because their vulvo-perineal cyclical pain increased during menstruation.

Of the 281 patients for whom a clinical examination was described, 97.5% were found to have a vulvo-perineal nodule, mass, or swelling, whereas only 2.1% presented with bluish cutaneous lesions and 0.4% with bilateral polyps of the labia minora.

All but one patient underwent surgical excision of their lesions; however, only 28.1% received additional hormonal therapy. The recurrence rate was 10.2% for a median follow-up period of 10 months, based on 61 studies.

One of the conclusions of the review is that in cases of anal sphincter involvement, perianal ultrasound should be performed. Also, surgical excision of the lesion should be performed to remove the lesion and confirm the diagnosis histologically.

“Hormonal treatment could be proposed to attempt to decrease the size of a large lesion before surgery or to avoid recurrence of the lesion,” wrote the authors.

Vulvo-perineal endometriosis presents mostly after perineal trauma, yet its precise etiology is unclear. Still, the disease might be separated between cystic and nodular lesions with distinct etiologies and treatment.

Direct mechanical implantation seems the most likely hypothesis to explain scar endometriosis after OB/GYN procedures, according to the authors, whereby “mechanical dissemination during normal vaginal delivery, for example, allows transplantation of viable decidual endometrial cells into the episiotomy wound or perineal tear.”

Scar endometriosis, however, also can occur after general surgical procedures like appendicectomy, inguinal hernial repair, and laparoscopic cholecystectomy or even after laparoscopic gastric bypass.

Among the various explanations of the pathogenesis of spontaneously developing perineal endometriotic lesions, the most likely is lymphovascular dissemination. But the presence of endometriosis in the labia majora could also result from the direct spread of pelvic endometriosis along the round ligaments or canal of Nuck remnants.

Immunological, genetic, and familial factors also may be implicated in the pathogenesis of this condition.

Due to the rarity of the disease and its variability in clinical presentation, the condition is hardly recognized by some health care professionals, leading to a delayed diagnosis.

The review found a mean duration of symptoms of 12 months, ranging from 2 weeks to 20 years, before the disease was correctly diagnosed.

Because an evidence-based approach to the diagnosis, treatment, and recurrence rate of affected patients remains a challenge due to low prevalence—coupled with the variations in management and limited quality of available studies—the authors propose a prospective database of vulvo-perineal endometriosis to increase knowledge and awareness among health care professionals and to optimize patient care.

Maillard C, Alami ZC, Squifflet JL, et al. Diagnosis and treatment of vulvo-perineal endometriosis: a systematic review. 

. Published online May 11, 2021. doi:10.3389/fsurg.2021.637180

Due to the rarity of the disease and its variability in clinical presentation, the condition is hardly recognized by some health care professionals, leading to a delayed diagnosis. 

Diagnosing and treating vulvo-perineal endometriosis

Clinicians should offer pregnant women effective behavioral counseling interventions aimed at promoting healthy weight gain and preventing excess gestational weight gain during pregnancy, according to a recommendation by the U.S. Preventive Services Task Force (USPSTF).

“Promoting healthy weight gain during pregnancy is important for both pregnant people and their babies,” said Task Force member Aaron Caughey, MD, MPP, MPH, PhD, a professor and chair of ob/gyn at Oregon Health & Science University in Portland.

 represents the first time the Task Force reviewed the evidence on how to help pregnant women maintain a healthy weight. “We found that counseling is effective and can be incorporated into prenatal care,” Caughey told 

The incidence of overweight and obesity has increased among women of childbearing age and those who are pregnant. In 2015, nearly half of all women began their pregnancy overweight (24%) or obese (24%).

Reported rates of overweight and obesity are higher among Black, Alaska Native/American Indian and Hispanic women, compared to White and Asian women.

While gaining a healthy amount of weight is an important component of pregnancy, “gaining too much weight can be harmful for pregnant people and their babies, which can lead to a higher risk of gestational diabetes, cesarean deliveries and babies who are born with a birth weight that is too high,” Caughey said. “The good news is that effective behavioral counseling interventions can help pregnant people gain a healthy amount of weight and avoid gaining too much weight.”

Counseling should occur throughout the pregnancy, rather than in a single discussion, according to Caughey, who also serves as associate dean for Women’s Health Research and Policy at the university. “After reviewing many different ways to support women who are pregnant in managing their weight, we found that effective counseling can include discussions during routine office visits, as well as strategies like nutrition education and exercise classes.”

The recommendation statement advocates that clinicians engage with their patients to determine an intervention that best fits the patient’s individual circumstance.

In general, counseling should start at the end of the first trimester or the beginning of the second trimester and end prior to delivery. Each encounter can vary from 15 minutes to 2 hours, comprising highly diverse interventionists, including clinicians, registered dietitians, qualified fitness specialists, physiotherapists and health coaches, across different settings like a local community fitness center.

“The health of all people nationwide is the Task Force’s main priority, and we recognize the challenges related to implementing recommendations in areas with limited access to health care and related services,” Caughey said.

Although effective counseling can help pregnant women gain a healthy amount of weight throughout their pregnancy, “important research gaps still exist,” Caughey said. “More research is needed to determine which types of counseling are most effective, the ideal number and length of counseling sessions, whether interventions should be tailored to specific populations, and any potential harms of counseling.”

Caughey also said that while these interventions can improve some health outcomes like gestational diabetes and unscheduled cesareans, “additional research is required to know how they affect other important outcomes, such as preterm birth.”

Caughey reports no relevant financial disclosures.

U.S. Preventive Services Task Force. Behavioral counseling interventions for healthy weight and weight gain in pregnancy: U.S. Preventive Services Task Force recommendation statement. 

. 2021;325(20):2087-2093. doi:10.1001/jama.2021.6949

Bob Kronemyer

Articles

Nemvaleukin monotherapy and with pembrolizumab for ovarian cancer

Predicting the age at natural menopause

Diagnosing and treating vulvo-perineal endometriosis

Behavioral counseling interventions for pregnancy weight