Lisa Astor

The use of MK-6482 (belzutifan) continues to induce strong clinical activity in patients with von-Hippel Lindau (VHL) disease-associated renal cell carcinoma, according to updated findings from a phase 2 study.

Moreover, the data, which were recently presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrated that the drug was effective against other VHL disease-associated tumors.

“This update continues to demonstrate the activity of (MK-6482) in patients with (VHL disease)-associated renal and non-renal tumors accompanied by an acceptable safety profile,” said study author Dr. Ramaprasad Srinivasan, head of the Molecular Cancer Therapeutics Section, Center for Cancer Research, National Cancer Institute.

Sixty-one patients (median age, 41 years; 52.5% males) who were diagnosed with VHL disease based on germline alteration who had at least one measurable renal cell carcinoma tumor, had not received any prior systemic anticancer therapy, did not have metastatic disease, and had an ECOG performance status of 0 or 1 (a patient’s level of functioning and ability to care for themselves with 0 being fully functioning and 4 being disabled).

As of data cutoff, which was at a median of 21.8 months after enrollment, 88.5% of patients were still receiving treatment.

Responses in target renal cell carcinoma lesions were observed in 30 patients; all of which were partial responses (a decrease in size of the tumor in response to treatment), and another four patients had unconfirmed partial responses. Stable disease was reported in 49.2% of patients and one patient was not evaluable. Ninety-two percent of patients had a decrease in target renal cell carcinoma lesion size.

The median time to treatment response was 8.2 months and the duration of response was not reached. The progression-free survival (time during and after treatment when the patient lives without disease progression) rate at 12 months was 98.3% and 96.5% at 24 months, however a median progression-free survival has not yet been reached.

In pancreatic lesions, responses were reported in 77% of patients, with complete responses (disappearance of all cancer in response to treatment) in 9.8% and partial responses in 67.2%. Among pancreatic neuroendocrine tumors, the objective response rate (or the rate of a measurable response to the treatment) was 90.9% with complete responses in 13.6% and partial responses in 77.3%. The objective response rate was 30% in central nervous system hemangioblastomas with complete responses in 6% and partial responses in 24%.

Sixty-nine percent of retinal hemangioblastomas were improved and 31% were stable as best response.

All patients reported a treatment-related side effect. Serious or severe side effects were observed in 32.8% of patients and life-threatening or fatal side effects occurred in 14.8%. Side effects led to discontinuation in 1.6% of patients and a side effect led to death in one patient, but it was not treatment related.

The most common side effects were anemia (90.2%), fatigue (65.6%), headache (41.0%), dizziness (39.3%) and nausea (34.4%). Most of the side effects were mild to moderate in severity, but common serious or severe side effects were anemia (8.2%) and hypertension (8.2%).

Recently, the Food and Drug Administration granted the drug a priority review for the treatment of patients with VHL disease–associated renal cell carcinoma who do not require immediate surgery based on earlier results of this study. A priority review is a program the agency established to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease.

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At a median follow-up of almost two years, 88.5% of patients remained on study treatment.

Novel Drug Induces Robust Responses in von-Hippel Lindau Disease-Associated Kidney Cancer

Treatment with Padcev (enfortumab vedotin-efjv) continues to be associated with better survival outcomes and responses to therapy in patients with advanced urothelial carcinoma who had previously received platinum-based chemotherapy and PD-1/PD-L1 inhibitors, compared to chemotherapy.

“(Padcev) is the first drug beyond chemotherapy and immunotherapy to show a significant survival advantage in previously treated advanced urothelial cancer,” said Dr. Thomas Powles, director of the Barts Cancer Centre in London, United Kingdom, in a presentation of the data during the virtual 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium. “This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited.”

received Food and Drug Administration (FDA) approval

 in December 2019 for the treatment of adults with locally advanced or metastatic urothelial cancer who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy. The accelerated approval was granted because treatment options are limited once urothelial cancer has progressed on both chemotherapy and immunotherapy. Data from the phase 2 EV-201 trial supported the approval.

This data comes from the open-label, randomized phase 3 EV-301 trial, which served as a confirmatory study for the benefit of Padcev over chemotherapy in this setting following the FDA approval.

A total of 608 patients (median age, 68 years) with histologically or cytologically confirmed urothelial cancer, including patients with squamous differentiation or mixed cell types, were enrolled onto the study, and randomized to receive either Padcev (301 patients) or chemotherapy (307 patients). Eligible patients had radiographic progression or relapsed during or after immune checkpoint inhibition for the treatment of advanced urothelial cancer and had received prior platinum-containing chemotherapy.

Patients in the chemotherapy arm received either docetaxel, paclitaxel or vinflunine.

Measuring overall survival (OS) was the main goal of the study. Other goals included assessing progression-free survival (the time from treatment to disease progression or worsening), objective response rates (the proportion of patients who had a complete or partial response to treatment) and safety.

Fourteen percent of the patient population was from the United States, 31% had liver metastases and 87% had received one or two previous lines of therapy.

As of data cutoff, 81% of patients had discontinued treatment in the Padcev arm versus 93% in the chemotherapy arm, which was due to progressive disease in 59% of patients in both arms. At a median follow-up of 11.1 months, the median treatment exposure was 5 months in the Padcev and 3.5 months in the chemotherapy arm.

The median OS with Padcev was 12.88 months versus 8.97 months with chemotherapy. Subgroup analyses for OS favored the Padcev arm for all groups except women, although Powles noted that some of the subgroups were too small to draw conclusions.

Median progression-free survival with Padcev was 5.55 months versus 3.71 months.

Confirmed objective response rate in the Padcev arm was 40.6%, which included complete responses in 4.9% of patients. In the chemotherapy arm, the objective response rate was 17.9% with complete responses in 2.7% of patients.

Treatment-related adverse event (TRAE) rates were similar between the two arms, with any-TRAE rates of 94% in the Padcev arm and 92% in the chemotherapy arm, and grade 3 or higher (more serious or severe) TRAE rates of 51% and 50%, respectively. TRAEs led to treatment discontinuation in 14% of patients in the Padcev arm and 11% in the chemotherapy arm.

Powles highlighted that the rate of grade 3 or higher maculopapular rash (flat and raised skin lesions) was increased in the Padcev arm (7% vs. 0%), whereas rates of grade 3 or higher neutrophil count decrease (6% vs 13%), white blood cell count decrease (1% vs 7%), and febrile neutropenia (1% vs 6%) were all higher in the chemotherapy arm.

TRAEs of special interest in the Padcev arm included rash (all grade, 44%; grade 3 or higher, 15%) and severe cutaneous adverse reactions (all grade, 20%; grade 3 or higher, 5%), peripheral neuropathy in terms of sensory events (all grade, 44%; grade 3 or higher, 4%) and motor events (all grade, 7%; grade 3 or higher, 2%), and hyperglycemia (all grade, 6%; grade 3 or higher, 4%). The majority of TRAEs of special interest were mild to moderate in severity.

Treatment with Padcev, compared to chemotherapy, continues to show better results in patients with advanced urothelial carcinoma who had previously received certain therapies. 

Padcev Continues to Show Promise in Patients with Previously Treated Bladder Cancer

MANY WOMEN WITH HORMONE-DRIVEN early breast cancer can forgo chemotherapy following surgery without worsening their chance of cure, thanks to a test that can pinpoint an individual’s need for the treatment. To help prevent cancer’s recurrence after surgery, women with this disease typically take endocrine treatments that suppress the body’s production or use of the hormone estrogen, and they often also receive chemotherapy. This post-surgical treatment is known as adjuvant therapy.

The tumor tissue test looks for 21 cancer-associated gene mutations and can determine which women have a low risk of recurrence and don’t need chemotherapy and which face a higher risk and can benefit from the treatment.

The findings, presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in June, were generated by the phase 3 TAILORx study. The data are expected to save thousands of women — about 70 percent of those with hormone-driven early breast cancer &mdash; from overtreatment with chemotherapy.

“These are very important data, because this is the most common form of breast cancer in the United States and developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all of its side effects and with its potential benefits,” ASCO expert Harold A. Burstein, M.D., Ph.D., of Boston’s Dana-Farber Cancer Institute, said following the presentation. “What the data provided here today show, from this massive National Cancer Institutesponsored trial, is that the vast majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”

The women who participated in the trial had hormone receptor-positive, early-stage breast cancer that did not overexpress the protein HER2. The cancer had not spread to their lymph nodes.

The median age of the participants was 55; 33 percent were 50 or younger. More than half of the patients (57 percent) had intermediate-grade disease, and 63 percent had a 1- to 2-centimeter tumor.

Estrogen receptor (ER)-positive, HER2-negative, nodenegative breast cancer is one of the most common types, accounting for up to 50 percent of cases of the disease, noted lead study author Joseph A. Sparano, M.D., the associate director for clinical research at the Albert Einstein Cancer Center in the Bronx, a bureau of New York City. Up to 30 percent of patients with these tumors typically experience a recurrence within 10 years of initial treatment. Although adjuvant chemotherapy is recommended for these patients, the benefit is typically very small. Across the board in this population without gene profiling, Sparano said, adding chemotherapy to endocrine therapy prevents 3 to 5 percent of the women from developing a breast cancer recurrence within 10 years of initial treatment, as compared with giving endocrine therapy alone.

The 21-tumor gene expression assay, Oncotype DX Breast Recurrence Score test, helps predict the benefit of chemotherapy based on patient scores from zero to 100. Patients with a score of 26 to 100 have a higher risk of recurrence and benefit from adding chemotherapy to endocrine therapy, whereas those with a score of zero to 10 (low risk) derive little, if any, benefit. It’s uncertain whether adding chemotherapy helps patients with scores of 11 to 25 (intermediate risk).

Between April 2006 and October 2010, 10,273 women were registered for the study, which is the largest adjuvant breast cancer trial to date, according to Sparano. “It was performed in six countries, four continents, over 1,100 sites … and includes a total of 30 co-authors,” said Sparano, who also serves as vice chair of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Research Group, which designed and conducted the study.

The participants who could be evaluated were divided into groups based on recurrence score. Those with a low score (1,629 patients) received endocrine therapy alone. Women with a high score (1,389) received endocrine therapy in combination with standard adjuvant chemotherapy.

Of 6,711 women with an intermediate score, 3,399 were randomized to receive just endocrine therapy, and 3,312 were randomized to receive the standard treatment of chemotherapy followed by endocrine therapy. The women were divided into subgroups based on menopausal status, planned chemotherapy, planned radiation and recurrence score groupings of 11 to 15, 16 to 20, and 21 to 25.

Sparano pointed out that the trial followed women in real time and reflected current standards for chemotherapy and endocrine therapy. Burstein added that prior studies employing the 21-gene test were based on older standards, such as age and tumor size and grade. Therefore, the new findings helped validate the role of adjuvant endocrine therapy with or without chemotherapy in the setting of modern regimens.

The study’s primary goal involved assessing rates of invasive-free survival, which refers to the amount of time before cancer spreads into healthy tissues. At nine years, patients with intermediate recurrence scores receiving endocrine therapy alone and chemotherapy followed by endocrine therapy had similar invasive-free survival rates, both close to and far from the disease’s original location. In these women, the invasive-free survival rate was 83.3 percent with endocrine therapy alone and 84.3 percent with endocrine therapy plus chemotherapy.

The two intermediate-score groups also had similar amounts of time without disease recurrence distant from the original site (94.5 percent with just endocrine therapy versus 95 percent with added chemotherapy); time without any recurrence (92.2 percent versus 92.9 percent); and overall survival (93.9 percent versus 93.8 percent).

Among patients with low recurrence scores, there was a 3 percent rate of distant recurrence (for example, spread of the cancer to the lungs, liver or bones) with endocrine therapy alone, and patients in the high-score group had a 13 percent rate of distant recurrence with added chemotherapy. A secondary analysis of the two mid-range recurrence score groups considered factors that may determine which patients would benefit from added chemotherapy. Although there was no significant association between recurrence score and menopause, tumor size or grade (a measurement of the abnormality of cancer cells based on how they look under a microscope), there was an association between recurrence score and age. In women 50 years or younger with a score of 16 to 20, there were 2 percent fewer distant recurrences among those who received chemotherapy compared with those who did not, and 7 percent fewer recurrences in those with a score of 21 to 25 who took chemotherapy versus those who did not.

“The younger women who had a recurrence score of 16 to 25 had some chemo benefit,” Sparano said. “This was information that could drive some younger women who have a recurrence score in this range to accept chemotherapy.”

The TAILORx trial once again confirmed that patients of any age with this type of breast cancer and a score of zero to 10 would be recommended for endocrine therapy alone (16 percent of patients), and all women in this population with a score of 26 to 100 (17 percent) would be recommended for added chemotherapy.

Women over age 50 with a score of 11 to 25 (45 percent) and patients 50 or younger who have a score of 11 to 15 (8 percent) should be given strictly endocrine therapy as an adjuvant treatment.

“In terms of the big picture of the impact on care, application of this test in clinical practice to this population would be estimated to spare chemotherapy in about 70 percent and to select chemotherapy in about 30 percent, on average,” Sparano said. Burstein added that, for the small group of women who are under age 50 and have intermediate scores from 20 to 25, there will be discussion about whether chemotherapy is warranted or whether using an alternative endocrine approach, such as ovarian suppression, might accomplish the same goals.

“The goal of this study was not just to use less treatment; the goal was to tailor treatment … with the idea of saying some women are going to need more of one kind of therapy and less of another, and others will get a different treatment based on the biology of their disease,” Burstein said. “So, this is an extraordinary day for breast cancer doctors and for women who have breast cancer. It allows us to individualize treatment based on extraordinary science, which now has tremendous prospective validation.”

Some women with hormone-driven early breast cancer can skip chemotherapy after surgery.

Avoiding the Chemo Chair

Pre-surgical (neoadjuvant) treatment with the immunotherapy combination Opdivo (nivolumab) plus Yervoy (ipilimumab) nearly tripled objective response rates (ORR) in patients with high-risk resectable melanoma, compared to single-agent therapy with the PD-1 inhibitor.

However, the treatment regimen did come with a cost, carrying a significantly higher rate of grade 3 adverse events (AE), according to a small study presented at the 2017 SITC Annual Meeting.

In the combination arm (11 patients), the ORR was 73 percent and 50 percent of patients achieved a pathological complete response (pCR). With Opdivo alone (12 patients), the ORR was 25 percent and the pCR rate was 25 percent. Unfortunately, these gains in response were accompanied by 73 percent of patients in the combination arm having a grade 3 AE compared with just 8 percent in the single-agent arm. This high level of toxicity led the researchers to close the study early, according to Sangeetha M. Reddy, M.D., MSci. Reddy worked on this trial with co-investigators Rodabe Amaria, M.D. and Jennifer Wargo, M.D.

"The initial trial was designed with 20 patients in each arm; however, the trial was stopped early after a data safety monitoring board review identified differences in efficacy and toxicity between treatment arms,” Reddy, a medical oncologist at The University of Texas MD Anderson Cancer Center, said during a presentation of the results. “Treatment with combination ipilimumab/nivolumab is associated with higher response rates in the neoadjuvant setting, but also with significant toxicity, suggesting we need to optimize this regimen further in this setting.”

In the trial, patients were stratified by stage and PD-L1 status for the combination of neoadjuvant Opdivo and Yervoy for up to three doses or neoadjuvant Opdivo monotherapy for up to four doses. Following resection, patients in both arms were then given adjuvant Opdivo for six months. In the neoadjuvant setting, the primary endpoint was pathological complete response (pCR) rate at surgical resection, and secondary endpoints were RECIST responses and toxicity. In the adjuvant setting, secondary endpoints included relapse-free survival (RFS), overall survival, and immune monitoring.  

Twenty-three patients were enrolled when the trial was halted. The median age of patients was 49 in the combination arm and 55 in the monotherapy arm. All patients had an ECOG performance status of 0. Many of the patients had received prior surgery (64 percent in the combination arm and 42 percent in the monotherapy arm) and few had received prior systemic therapy (18 percent and 8 percent, respectively). A majority of the patients demonstrated PD-L1 expression (at least 1 percent; 64 percent and 75 percent, respectively); patients were also tested for 

 (36 percent and 58 percent, respectively) and 

 mutations (27 percent and 8 percent, respectively).

RFS was improved with the combination compared with Opdivo alone and among patients who achieved a pCR versus those who did not. In addition, greater clonality of T-cell populations was demonstrated in patients who achieved a response, and less remodeling of the T-cell repertoire was noted in patients who received Opdivo alone and achieved a response.

Patients also underwent molecular and immune profiling for translational studies, and the researchers noted higher CD8 and PD-L1 expression in responders at baseline and following treatment, as well as enhanced immune infiltrates in these patients. “Preliminary biomarkers of response are in line with those already identified, and additional analyses are underway to identify novel biomarkers of response,” Reddy said.

The most common grade 3 AEs with the combination were transaminitis, colitis, hyperthyroidism and myositis, compared with monotherapy, where the only grade 3 AE was tumor-related pain. No grade 4 toxicities were noted in the neoadjuvant portion of the trial. Seven patients in the combination arm were unable to receive the full dose, six required steroids, and three required a delay in their surgery.

Reddy noted that further analysis is ongoing and is expected to be shared in the next few months that will determine the next steps with this study.

Treatment with Opdivo (nivolumab) plus Yervoy (ipilimumab) improved response rates in patients with melanoma, but not without some severe side effects.

Lisa Astor

Novel Drug Induces Robust Responses in von-Hippel Lindau Disease-Associated Kidney Cancer

Padcev Continues to Show Promise in Patients with Previously Treated Bladder Cancer

Avoiding the Chemo Chair

Immunotherapy Combination Improves Melanoma Outcomes, But at a Cost

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