Use of antibiotics up to a month before treatment with a checkpoint inhibitor may decrease the efficacy of the immunotherapy agent, results of a retrospective analysis show. The analysis, presented during a presscast of the 2017 Genitourinary Cancers Symposium, raised suspicion of the relationship between gut microbiota and antibiotics and their effect on immune checkpoint blockade agents.

In patients with metastatic renal cell carcinoma (mRCC), patients who had received broad-spectrum antibiotics had a shorter median progression-free survival (PFS) rate when treated with checkpoint inhibitor immunotherapy than those who had not received antibiotics of 2.3 versus 8.1 months, respectively (

Previous preclinical studies using mouse models have suggested an association between antibiotics and the efficacy of immune checkpoint blockade agents.

 “This is the first analysis evaluating the impact of antibiotics on outcome in mRCC patients treated in the era of immune checkpoint blockade,” said investigator Lisa Derosa, MD, PhD candidate, of the Gustave Roussy Cancer Institute, Paris-Sud University in Villejuif, France.

Researchers analyzed 80 patients with mRCC who were being treated with checkpoint inhibitors on trials at the Gustave Roussy institute. Immunotherapy treatments included single-agent anti—PD-1/PD-L1 therapy (n = 67), a combination of a PD-1 inhibitor and a CTLA-4 inhibitor (n = 10), and a combination of anti–PD-L1 therapy and bevacizumab (Avastin; n = 3).

A majority of the enrolled patients were male (65%), 88% had a clear-cell histology, and 80% of the patients had prior nephrectomy. Twenty-one percent had favorable disease by International mRCC Database Consortium (IMDC) risk standards, 57% had intermediate IMDC risk, and 22% had poor-risk disease. Sixteen patients (20%) had received antibiotics up to 1 month prior to starting treatment with immunotherapy, including mostly beta-lactamases or fluoroquinolones.

At a median follow-up of 6 months, overall survival (OS) results were not yet able to be reached in the overall population, but a negative trend was already noted for patients who received prior antibiotics. The objective response rate also favored patients who had not received antibiotics (

In a subgroup of 62 patients who were treated with nivolumab (Opdivo) monotherapy, patients who had not taken antibiotics showed a greater PFS rate, which also achieved statistical significance (

 <.009). OS in the nivolumab monotherapy subgroup was also significantly higher in patients who had not taken recent antibiotics (

“Derosa shows that antibiotic therapy may have a direct impact on how well the PD-1 inhibitor nivolumab works in patients with kidney cancer,” said Sumanta K. Pal, MD, who moderated the presentation.

A multivariate analysis for prognostic risk factors showed a hazard ratio of 4.17 (95% CI, 1.92-9.08) for patients who had not received antibiotics compared with those that had taken antibiotics (

 <.001). Patients with a lower Karnofsky performance statuses also showed an increased hazard ratio (HR, 5.23; 1.57-17.4; 

“Immune based therapies for cancer may have a complex interplay with the host’s microbiome,” commented Pal, an assistant clinical professor in the Department of Medical Oncology and Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope in Duarte, California. “Antibiotics may influence the bacterial composition of our gut, and this could in turn impact how effective immune therapy is.”

Derosa stated that the data was preliminary but that it encouraged longer follow-up and further studies to confirm the hypothesis of the study.

“The observations that Derosa makes have some consistency with preclinical observation,” Pal said. “We may be able to offer some insights as to whether or not bacterial composition of the gut could affect clinical outcomes and that might help us guide antibiotic usage.” Pal also suggested that these findings are not yet mature enough to impact clinical practice. The researchers plan to enroll additional patients in this study to investigate the mechanism of action. Other studies exploring the relationship between antibiotics and the efficacy of immunotherapy agents in lung cancer and kidney cancer are ongoing.

Derosa L, Routy B, Enot D, et al. Impact of antibiotics on outcome in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. Presented at: 2017 Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abstract 462.

Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. 

. 2015;350(6264):1079-1084. doi: 10.1126/science.aad1329.

Articles

A recent study presented at the 2017 Genitourinary Cancers Symposium found that use of antibiotics could damper the efficacy of checkpoint inhibitors, potentially due to the relationship between gut microbiota and antibiotics.

Using Antibiotics Could Affect Checkpoint Inhibitors

Women who are experiencing symptoms of menopause are less likely to adhere to treatment, according to findings presented at the 2016 San Antonio Breast Cancer Symposium.

 Better addressing patient concerns prior to treatment may help prevent the misattribution of menopausal symptoms to side effects from treatment, said lead investigator Samuel G. Smith, PhD.

“Communicating the likelihood of experiencing those symptoms is important,” said Smith, a Cancer Research UK postdoctoral fellow and university academic fellow at the University of Leeds. “What would be particularly interesting would be to look at all of the symptoms that were reported in trial arms [of this and similar trials] compared with placebo arms of each trial to look at what were naturally occurring symptoms and what were actually triggered by those particular therapies, and that way you can communicate more accurate information to patients so they can make an informed decision about whether or not they want to participate.”

Nine randomized trials have studied the effect of selective estrogen receptor modulators on the prevention of breast cancer, and have shown a reduction in the incidence of breast cancer by at least 30%, said Smith. In the IBIS-1 trial, extended analysis showed that 5 years of tamoxifen treatment can reduce the incidence of breast cancer for at least 20 years.

This analysis of patients enrolled in the IBIS-1 explored whether women experiencing menopausal symptoms were likely to adhere to their assigned treatment of tamoxifen or placebo for a period of 4.5 years.

Across both arms of the trial, 66.8% of women adhered to treatment, meaning that they remained on either tamoxifen therapy or placebo for 4.5 years (odds ratio, 1.53; 95% CI, 1.34-1.75; 

 <.0001). Women receiving tamoxifen (n = 1987) were less likely to adhere to treatment than women in the placebo arm (n = 2000) at a rate of 62.1% versus 71.5%, respectively.

Among women aged 35 to 70 at an increased risk of developing breast cancer in the United Kingdom, women experiencing menopausal symptoms including nausea/vomiting; gynecologic symptoms, such as irregular bleeding, vaginal dryness, or vaginal discharge; headaches; and hot flashes were included in the analysis. Symptoms were assessed prior to trial entry and at 6 months.  

Characteristics were well matched across the 2 arms at baseline. The median age of the patients was 49 and a majority of patients had a family history of at least 2 family members affected by breast cancer. In each arm, patients had a median Tyrer-Cuzick risk of 5.7% of developing breast cancer (

Overall, symptoms of nausea/vomiting were experienced by 5% of patients, headaches by 7%, hot flashes by 31.5%, and gynecologic symptoms by 20.9%. Most of these symptoms were mild, yet hot flashes at moderate levels were noted in 8.7% and at severe levels in 5.1%.

Of the women who reported nausea/vomiting, 53.7% adhered to either treatment (

 <.001) and 58.6% of women reporting headaches adhered to treatment (

 = .01). Smith indicated that there was no relationship between hot flashes or gynecologic symptoms and adherence.

When stratified by trial arm, it was demonstrated that patients reporting nausea/vomiting in either arm of the trial were less likely to adhere to their assigned treatment, whereas patients reporting headaches who were receiving placebo were less likely to adhere to treatment, but this was not noted in the tamoxifen arm. Patients with gynecologic symptoms were less likely to be adherent in the tamoxifen arm, but not in the placebo arm.

“Tests of heterogeneity revealed that these effects of symptoms on adherence were comparable between the trial arms,” noted Smith.

Smith noted that increased interventions are needed to manage menopausal symptoms for women on these trials.

“Dropout rates were fastest within the first 6 to 12 months, indicating that this is an optimal time in which to deliver such interventions,” Smith said.

Moderator Kent Osborne, MD, director of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine, noted that while many methods now exist to ease these menopausal symptoms, most of these options—including venlafaxine HCI (Effexor) or other antidepressants to reduce hot flashes or acupuncture&mdash;were not known when the IBIS-1 trial was started over 20 years ago.

Perhaps recommending these methods for women experiencing menopausal symptoms could reduce the level of nonadherence to breast cancer prevention treatments.

Smith SG, Sestak I, Howell A, Forbes J, Cuzick J. Menopausal symptoms as predictors of long-term adherence in the International Breast Cancer Intervention Study (IBIS-1). Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S5-03.

Cuzick J, Sestak I, Cawthorn S, et al; IBIS-1 Investigators. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-1 breast cancer prevention trial. 

. 2015;16:67-75. doi: 10.1016/S1470-2045(14)71171-4.

Women experiencing symptoms of menopause are less likely to adhere to treatment.

Easing Menopausal Symptoms May Improve Adherence to Breast Cancer Prevention

The addition of everolimus (Afinitor) to fulvestrant (Faslodex) significantly improved progression-free survival (PFS) in postmenopausal patients with metastatic hormone receptor (HR)—positive, HER2-negative breast cancer who are resistant to aromatase inhibitor (AI) therapy, according to findings from the phase II PrECOG 0102 trial presented during a press conference at the 2016 San Antonio Breast Cancer Symposium.

In the study, the everolimus/fulvestrant combination doubled median PFS rates compared with fulvestrant alone, from 5.1 months on fulvestrant to 10.4 months with the combination (HR, 0.60; 95% CI, 0.40-0.92; P = .02).

“We feel that the study provides additional evidence that adding everolimus to anti-estrogen therapy in AI-resistant disease improves clinical outcomes,” said Noah S. Kornblum, MD, assistant professor of medicine, Albert Einstein College of Medicine, and attending physician of medicine, Montefiore-Einstein Center for Cancer Care.

The authors had hypothesized that the combination of everolimus and fulvestrant could be used to treat AI-resistant disease, which usually develops in most patients with HR-positive breast cancer treated with AI therapy. Researchers have shown that AI resistance can be overcome by targeting the PI3K-AKT-mTOR pathway,

 as seen in the phase III BOLERO-2 trial of everolimus and exemestane (Aromasin) in patients with HR-positive advanced breast cancer and resistance to AI therapy.

In the BOLERO-2 trial, the addition of the mTOR inhibitor to exemestane improved PFS rates from 3.2 months on exemestane alone to 7.8 months with the combination (

<.0001). The combination was approved in 2012 for the treatment of postmenopausal women with advanced HR-positive, HER2-negative breast cancer, largely based on results from the BOLERO-2 trial.

The patient population in the PrECOG trial were similar to those in the BOLERO-2 study, yet Kornblum believes that patients in the PrECOG placebo arm may have had longer PFS rates than those in the BOLERO-2 placebo arm due to the superiority of high-dose fulvestrant over exemestane.

“There are some potential advantages of fulvestrant in some people’s minds over steroidal AIs, such as exemestane,” Kornblum said. We don’t really have a direct comparison of these 2 combinations, but I think [fulvestrant and everolimus] does offer some [additional] options and it’s nice to have great options.”

Patients in the PrECOG trial were eligible if they had relapsed while on adjuvant AI therapy or had progressed after an AI therapy for metastatic disease, had an ECOG performance status score of 0 or 1, and had previously received no more than 1 chemotherapy regimen.

The 130 patients were randomized 1:1 in the induction phase to receive either high-dose fulvestrant in addition to 10 mg of everolimus or fulvestrant with matching placebo. Patients continued treatment until progression or unacceptable toxicity for a maximum of 48 weeks. After 48 weeks, patients moved on to the continuation phase and could continue treatment of fulvestrant with or without everolimus.

The combination was associated with additional toxicity compared with the fulvestrant-alone arm with grade 3 adverse events (AEs) occurring in 48% of patients in the combination arm versus 14% in the fulvestrant group. The most common grade 3 AEs in the combination arm included stomatitis in 9% of patients, pneumonitis in 6%, fatigue in 5%, and hyperglycemia in 6%.

The safety profile of the everolimus/fulvestrant combination was consistent with that of the everolimus/exemestane combination in the BOLERO-2 trial. Yet Kornblum said that clinicians are all “learning on the fly, somewhat, how to manage the safety and toxicity profiles for these combinations.”

For instance, Kornblum noted that in the trial supportive care with prophylactic corticosteroid mouthwash was not used, which could have possibly prevented the frequency of cases of stomatitis as recent data has shown that the use of corticosteroid mouthwash reduces the risk of low-grade stomatitis. “That information was not known at the inception and conduction of this study,” he said.

Kornblum NS, Manola J, Klein P, et al. PrECOG 0102: A randomized, double-blind phase II trial of fulvestrant plus everolimus or placebo in post-menopausal women with hormone-receptor positive, HER2-negative metastatic breast cancer resistant to aromatase inhibitor therapy. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S1-02.

Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 2015;15(5):261-275.

Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. 

According to phase II trial findings, adding everolimus to fulvestrant significantly improved progression-free survival for postmenopausal patients with metastatic hormone receptor-positive, HER2-negative breast cancer who are resistant to aromatase inhibitor therapy.

Lisa Miller

Articles

Using Antibiotics Could Affect Checkpoint Inhibitors

Easing Menopausal Symptoms May Improve Adherence to Breast Cancer Prevention

Everolimus/Fulvestrant Combo Improves Survival in HR+ Breast Cancer

Lisa Miller

Articles

Using Antibiotics Could Affect Checkpoint Inhibitors

Easing Menopausal Symptoms May Improve Adherence to Breast Cancer Prevention

Everolimus/Fulvestrant Combo Improves Survival in HR&#43; Breast Cancer

Everolimus/Fulvestrant Combo Improves Survival in HR+ Breast Cancer