Virginia Powers, Ph.D.

What do people who have primary and recurrent ovarian cancer expect from maintenance therapy? A survey of about 1,950 people who chose to move forward with maintenance therapy revealed that most of them were expecting to buy time — at least 6 months’ delay in disease progression.

Maintenance therapy is based upon the understanding that patients achieving clinical remission following surgery and chemotherapy for ovarian cancer have a 60 to 70 percent chance of developing recurrent disease with 2 years, according to Jalid Sehouli, M.D., of the Charité Universitätsmedizin Berlin in Berlin, Germany. Several clinical trials have shown promise with various drugs but guidelines are still under development.

“We wondered what was important in choosing to undergo maintenance therapy and decided to ask the patients themselves,” Sehouli said.

The survey was disseminated to patients participating in the randomized double-blind trial.

Patients with ovarian cancer were unified in their responses regardless of age, disease stage, or whether they had primary or recurrent disease, and were more likely to opt to receive maintenance therapy if it could offer delay of disease progression and allow patients to maintain or improve their quality of life (QoL), according to findings from a survey reported at the European Society of Gynaecological Oncology (ESGO) 2017 Congress.

In all, 1,954 patients from centers in 10 European and Eastern European countries responded to the survey. The majority (67 percent) was aged 51 to 70 years. Primary ovarian cancer was diagnosed in 49.6 percent of patients, 36.3 percent had relapsed ovarian cancer and the disease stage was unknown for 6.9 percent of respondents. The International Federation of Gynecology and Obstetrics (FIGO) stage of the primary disease was 3 to 4 in 43.7 percent of respondents, unknown in 32.1 percent, and 1 to 2 in 14.3 percent. Most respondents (64.3 percent) were currently undergoing treatment, but this treatment consisted of a maintenance regimen for just 29.3 percent.

Regarding living situation, 81.7 percent of respondents did not live alone, and 61.4 percent said that they took tablets daily for comorbidities. Of these, patients reported that they took a mean of 3.3 tablets (range, 5 to 35 tablets) per day.

“Comedication and patient age do not seem to negatively influence patients’ preference towards maintenance therapy,” Sehouli noted.

The investigators found that patient age, prior surgery and living situation did not associate significantly with the respondents’ choice to undergo maintenance therapy.

However, patients receiving maintenance therapy had FIGO stage 3 to 4 disease at the primary diagnosis significantly more often, and also had recurrent disease.

However, age did play a role in disease management. Whereas there was no difference between older and younger patients receiving chemotherapy for their disease, fewer patients aged 70 years and older underwent surgery for their tumor. In addition, patients aged 70 or more years were more likely to live alone, and more often had FIGO disease stage 3 to 4. Patients in this age group also took significantly more tablets daily for co-morbidities.

Few Respondents Reported Bad Health Status

“Only a few patients under maintenance therapy described their health status as bad,” said Sehouli.

A positive note resounded when just 2 percent and 7 percent of patients currently undergoing maintenance therapy regarded their current state of health as very bad or bad, respectively. Most patients (37 percent) responded neutral, 35 percent said well and nearly 20 percent of patients described their current health status as very well.

Regarding patients’ expectation for maintenance therapy, 50 percent of patients with recurrent disease and 45 percent of patients with primary disease responded that they anticipated maintenance therapy to prevent disease progression for 6 months, and this expectation was similar in both older and younger patients. Just over 30 percent of primary cancer patients and 20 percent of patients with recurrent disease expected maintenance therapy to delay disease recurrence by 6 to 12 months, and fewer than 5 percent of patients with each disease stage anticipated progression delay of 24 to 36 months with maintenance therapy. Again, age played no role in the expectation of disease progression delay with maintenance.

Importantly, the patients expressed preferences for the delivery of maintenance therapy; 42.9 percent of respondents preferred oral tablets, 32.1 percent had no preference and 25 percent of patients preferred intravenous administration. An equal 35 percent of patients preferred a regimen of daily oral therapy and intravenous administration every three weeks. Just under 20 percent of patients preferred twice daily oral administration, 7 percent preferred weekly infusion and less than 3 percent stated they would like an ‘other schedule.’

Patients were quite knowledgeable about the types of side effects that could be experienced, and voiced their concerns about which were least tolerable. The side effects of most concern reported by between 35 and 40 percent of patients were polyneuropathy, nausea, hair loss and vomiting. Approximately 25 percent of patients were concerned about fatigue and the risk of infection, while 20 percent of respondents cited edema and high blood pressure as undesirable side effects. Less than 20 percent of patients listed neutropenia, constipation, diarrhea, stomachache, skin rash, anemia and bleeding disturbances as the side effects of most concern. This panel was similar between patients with primary or recurrent disease and among both younger and older patients.

The personal objective most patients listed for choosing a maintenance therapy were increasing the chance of effecting a cure (75 percent) improved quality of life (QoL; 14 percent), non-deterioration of QoL (40 percent), tumor shrinkage (45 percent of patients with recurrent disease vs 32 percent of primary disease patients) and decreased CA-125 (40 percent or less).

There was a consensus that maintenance therapy should delay tumor progression by 6 or more months; more than 60 percent of patients with primary or recurrent disease, and both older and younger patients expressed this as the main deciding factor for maintenance therapy.

“There is a high need for more information and patient education regarding maintenance therapy goals and side effects,” said Sehouli.

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Many patients who completed the survey felt maintenance therapy would help them buy time.

Survey Asks Why Some Ovarian Cancer Patients Choose Maintenance Therapy

More post-surgery surveillance is not necessarily better for patients with early-stage non-small cell lung cancer, according to a recent study.

Expanding surveillance after surgery from chest X-ray to follow-up with PET-CT scan did not improve overall survival (OS), researchers reported during the 2017 ESMO Congress.

Although most current guidelines recommend follow-up by chest X-ray every six months for two to three years with PET-CT allowed only when abnormalities are detected, several guidelines do recommend follow-up by PET-CT; however, evidence from a randomized trial to support either of these recommendations is lacking.

A final analysis done at a median follow-up of eight years and 10 months showed a trend toward improved OS in the experimental (maximal) follow-up arm, but did not significantly differ between minimal and maximal follow-up; median OS was 99.7 months compared to 123.6 months.

The three-year OS rates were 77.3 percent with minimal and 76.1 percent with maximal follow-up. The five- and eight-year OS rates were 66.7 versus 65.8 percent and 51.7 percent versus 54.6 percent in the minimal versus maximal arms, respectively.

Virginie Westeel, M.D., Ph.D., Thoracic Oncology, University Hospital of Besançon, France, and colleagues conducted the phase 3 IFCT-0302 trial (

) to evaluate which follow-up regimen could improve patient outcomes. They contrasted a minimal follow-up comprising physical examination together with history and a chest X-ray with a maximal follow-up that added CT scan with contrast of the thorax and upper abdomen plus fiber optic bronchoscopy, which was optional for patients with adenocarcinoma but mandatory for squamous and large cell carcinoma.

“Although the primary endpoint was not met, a longer follow-up is needed to avoid missing a potential long-term OS benefit of CT-scan—based surveillance,” commented Westeel.

Median disease-free survival (DFS) was not reached (NR) in the minimal cohort versus 59.2 months in the maximal cohorts. The three- and five-year DFS rates were 63.3 percent and 54.1 percent in the minimal arm compared to 60.2 percent and 49.7 percent in the maximal arm.

However, DFS favored the maximal follow-up in a subset of patients who did not experience disease recurrence at 24 months. The investigators reported results from an exploratory analysis that showed median OS of 129.3 with minimal follow-up versus OS NR with maximal follow-up in patients with no recurrence at 24 months. In patients with a recurrence at 24 months, median OS was 48.3 versus 48.4 months, respectively.

Westeel commented, “This is the first large randomized trial to evaluate follow-up after surgery for NSCLC. Although no significant survival benefit was seen, there was a trend for an earlier diagnosis of recurrences and second primary cancers suggesting that maximal follow-up with CT scan may have a potential long-term benefit for patients at high risk for second primary cancers.”

The IFCT-0302 study was a multicenter trial that randomized 1,775 patients with completely resected NSCLC to the minimal (888 patients) or maximal (887 patients) follow-up programs.

These regimens were repeated every six months after randomization during the first two years, and yearly until five years in both arms.

The primary endpoint of the trial was OS and two interim analyses were planned.

All patients had undergone resection for clinical stage 1, 2, 3A or T4 (pulmonary nodules in the same lobe of the lung) N0-2 NSCLC. All perioperative treatments were allowed but patients with renal impairment or with a prior history of breast cancer or melanoma were excluded from the study.

Patient characteristics were well-balanced between the two arms. Overall, 76.3 percent of patients were male with a median age of 63 years (range, 34-88 years), and 39.5 percent of patients had squamous and large cell carcinomas. Stage 1, 2 and 3 disease was reported in 68.1 percent, 13.7 percent, and 18.3 percent of patients, respectively. Most patients (86.6 percent) had undergone lobectomy (surgical removal of a lobe on the lung) or bilobectomy (surgical removal of two lobes on the right lung), with 8.7 percent also receiving pre- and/or post-operative radiotherapy, and 45 percent received pre- and/or post-operative chemotherapy. Histology included squamous (34 percent), adenocarcinoma (57 percent), and large cell (5.5 percent).

Discussant Egbert F. Smit M.D., Ph.D., Netherlands Cancer Institute in Amsterdam, The Netherlands, who was not involved in the study, commented, “The debate between chest X-ray versus CT-based follow-up after resection of early-stage NSCLC remains unsettled; additional data are needed to abandon CT-based follow-up during the first two years of resection.”

No Benefit in Increased Surveillance After Lung Cancer Surgery

Keytruda (pembrolizumab) produced better overall survival (OS) rates than chemotherapy for patients with recurrent, advanced urothelial carcinoma, according to a phase 3 KEYNOTE-045 study presented at the 2017 European Society of Medical Oncology (ESMO) Congress.

As of the cutoff point on May 19, 2017, median follow-up was 22.5 months in both arms. The median OS was significantly longer with Keytruda compared to chemotherapy in the overall patient population; median OS was 10.3 versus 7.4 months, respectively.

Significantly improved OS was observed regardless of the level of PD-L1 expression — a biomarker associated with better responses to Keytruda – as measured by combined positive score (CPS), with patients having CPS 10 percent or higher demonstrating a median OS of 8.9 with Keytruda versus 5.2 months with chemotherapy.

The 18-month OS rates were 33.2 percent compared to 19.7 percent with Keytruda versus chemotherapy, respectively.

Ronald de Wit M.D., Ph.D., group leader of the experimental systematic therapy of urogenital cancers program at Erasmus MC Cancer Institute, Rotterdam, Netherlands, presented mature results from the phase 3, multicenter, open label KEYNOTE-045 trial (

), which randomly assigned 270 patients with recurrent, advanced urothelial carcinoma to Keytruda at 200 mg every three weeks and 272 patients to investigators’ choice of chemotherapy (paclitaxel [Abraxane], docetaxel [Taxotere], or vinflunine [Javlor]).

Importantly, OS was longer with Keytruda versus chemotherapy regardless of age, liver metastases, hemoglobin levels, the presence of visceral disease and the choice of chemotherapy.

“Pembrolizumab is the first agent to improve survival over chemotherapy in the second-line setting. Not all patients benefit from checkpoint inhibition, but a sizeable proportion of patients who respond have very durable responses, even well over one year,” noted de Wit. “These resulting are striking in the setting of urothelial cancer, which is highly lethal in the metastatic state.”

Similar progression-free survival (PFS) was observed between the treatments; median PFS was 2.1 versus 3.3 months with Keytruda versus chemotherapy, respectively.

 The objective response rate (ORR) was nearly doubled with Keytruda; ORR was 21.1 percent with Keytruda versus 11.0 percent with chemotherapy. The responses with Keytruda were more durable than with chemotherapy; the median response duration of response was not reached in the Keytruda arm versus 4.4 months.

Furthermore, no new safety signals for Keytruda were raised, which had a superior long-term safety profile versus chemotherapy.

“Treatment-related adverse events [TRAEs] of any grade occurred in 62 percent of pembrolizumab-treated patients compared to 90.6 percent of those treated with chemotherapy,” noted de Wit. The incidence of grade 3 or higher TRAEs was 16.5 percent versus 50.2 percent, respectively. Immune-related AEs occurred in 19.5 percent of patients on Keytruda compared to 7.5 percent of patients on chemotherapy. Discontinuation due to an AE occurred in 7.1 percent versus 12.5 percent of Keytruda versus chemotherapy patients, respectively.

“The US Food and Drug Administration [FDA] approved pembrolizumab in May 2017 for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy,” noted de Wit. “Also, in July 2017, the FDA granted an accelerated approval to frontline pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.”

The KEYNOTE-45 trial was sponsored by Merck & Co, based in Kenilworth, New Jersey.

Keytruda (pembrolizumab) produced better overall survival (OS) rates than chemotherapy for patients with recurrent, advanced urothelial carcinoma.

Keytruda Bests Chemotherapy in Overall Survival Rates for Bladder Cancer

Several subtypes of difficult-to-treat sarcomas may respond to treatment with PD-1 pathway inhibiting immunotherapies, according to results presented at the 2017 European Cancer Congress of an immunohistochemistry (IHC) analysis of a large patient population.

Researchers evaluated the expression and clinical association of the key molecules in the PD-1 pathway and its primary ligand, PD-L1, on tumors and on cells in the tumor microenvironment of pediatric and young adult patients with sarcoma. The investigators also looked for the presence of CD8 expression on the tumors and on cells in the microenvironment, which has been associated with superior survival for patients with localized osteosarcoma.

PD-1/PD-L1 expression is only just beginning to garner attention in sarcoma subtypes, says Anke van Erp, Ph.D., M.Sc., of the Radboud University Medical Center in Nijmegen, the Netherlands.

“The interaction of PD-1 and PD-L1 results in negative regulation of T-cell activity, which can be blocked by PD-1 antibodies,” she explained.

With her colleagues, van Erp used IHC to evaluate protein expression on primary tumor samples of 217 patients who were stratified by age at diagnosis into cohorts of younger than 18 years and 18 years and older. They evaluated formalin-fixed paraffin-embedded tumor sections of 52 primary osteosarcoma samples, 22 Ewing sarcoma (ES), 42 alveolar rhabdomyosarcoma (ARMS), 80 embryonal RMS (ERMS), 29 synovial sarcoma (SyS) and nine desmoplastic small round cell tumor (DSRCT) patient samples by IHC for the expression of PD-1 (using clone MRQ-22), PD-L1 (clone E1L3N), and CD8+ cells (clone C8/144B). Samples having fewer than 10 percent positively staining cells for each marker were classified as negative and positive if samples showed 10 percent to 50 percent of stained cells. Samples with at least 50 percent stained cells for PD-1, PD-L1 or CD8 were determined highly positive for the specific marker.

The investigators found that cell surface PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor subtype and was most abundant in DSRCT, where it was expressed by 100 percent of tumor cells. PD-1 tumor cell expression was expressed on 19 percent of osteosarcoma and ES tumor cells but not on the other subtypes investigated in this series. PD-1 was expressed on 17 percent of infiltrating lymphocytes in SyS and at levels of 6 percent or less on the lymphocytes of osteosarcoma, ARMS and ERMS samples but not by the other subtypes. PD-L1 expression was highest (18 percent) in ARMS, followed by 16 percent on ERMS, 13 percent DSRCT and 8 percent in osteosarcoma samples. No PD-L1 expression was seen in SyS or ES samples.

CD8+ expressing cells were found in all subtypes, including in 76 percent of DSRCT samples, 66 percent of osteosarcoma, 43 percent SyS, 41 percent ES and in 39 percent of ERMS samples. In the DSRCT subtype, 13 percent of the samples had all three markers compared to osteosarcoma wherein just 2 percent of the specimens showed this same staining.

When the investigators explored the association of expression with the clinical outcome of overall survival (OS) at a follow-up of 100 months in sarcoma patients overall, they found no significant association between OS and expression of PD-1, PD-L1, or CD8.

However, they did find a strong correlation in the ARMS subtype where PD-L1 tumor expression significantly correlated with better OS and event-free survival in patients compared with patients with tumors expressing low or no PD-L1.

The investigators also identified ES patients aged 18 years or older with tumors expressing PD-1 as a cohort that was associated with poorer EFS.

Further evaluation of PD-1, PD-L1, and CD8+ expression in patients with sarcoma and metastatic disease is planned. “This research was limited by small samples of these relatively rare sarcoma subtypes but we were able to demonstrate that PD-1and PD-L1 expression and clinical association in sarcoma is subtype dependent; PD-L1 expression in ARMS correlates with better OS and EFS and PD-1 expression on ES and DSRCT tumor cells correlates with worse EFS,” van Erp summarized.

Van Erp noted that this was the first time that high levels of PD-1 expression, either alone or in combination with PD-L1, were demonstrated on the tumors of DSRCT patients, who also showed co-expression of CD8+ cells. Co-chair of the session, Stefan Sleijfer of the Erasmus Medical Center in the Netherlands agreed that the high levels of PD-1, PD-L1, and CD8 expression in DSRCT warrants further investigation into whether PD-1 blockade could have clinical benefit in DSRCT patients.

Patients with certain types of sarcoma may benefit from PD-1 blockades, according to a recent study.

Virginia Powers, Ph.D.

Survey Asks Why Some Ovarian Cancer Patients Choose Maintenance Therapy

No Benefit in Increased Surveillance After Lung Cancer Surgery

Keytruda Bests Chemotherapy in Overall Survival Rates for Bladder Cancer

PD-1 Blockades Show Potential in Sarcoma

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