Gina Mauro

The novel drug pimitespib was associated with significant survival outcome improvements in patients with advanced gastrointestinal stromal tumor (GIST) whose disease stopped responding to Gleevec (imatinib), Sutent (sunitinib) and Stivarga (regorafenib), compared to treatment with placebo.

The data, which were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrated that treatment with the study drug led to a 49% reduction in the risk of disease progression or death. Moreover, pimitespib was also associated with improved survival in patients whose disease harbors KIT exon 13/14 and 17/18 mutations.

“This trial demonstrated that pimitespib significantly improved (progression-free survival and prolonged overall survival with) a tolerable safety profile, (with) an HSP90 inhibitor, for the first time,” lead study author Dr. Yoshitaka Honma, of the National Cancer Center Hospital in Tokyo, Japan, said in during a presentation of the findings. “Pimitespib represents a potential new standard treatment in patients with GIST in the salvage-line setting, with a mechanism of action (that differs) from traditional therapies.”

An estimated 90% of GIST cases harbor driver mutations in KIT and PDGFRA, which promotes continuous oncogenic signaling. Although Qinlock (ripretinib) and Ayvakit (avapritinib) are both available in the treatment of patients with GIST and target those driver mutations, they may have limited efficacy.

Pimitespib, a novel HSP90 inhibitor, has shown prior antitumor activity in molecularly defined subgroups of solid tumors.

Here, the authors presented results from the CHAPTER-GIST-301 study, which enrolled patients with histologically confirmed advanced GIST whose disease did not respond to treatment with Gleevec, Sutent and Stivarga.

Participants were randomized to receive either study drug (54 patients) or placebo (27 patients).

Of note, patients whose disease progressed during the “blinded” portion of the study were “unblinded” and permitted to cross over and receive study drug.

Measuring progression-free survival (time during and after treatment when the patient lives without disease progression) was the main goal of the study. Other goals included assessing overall survival (length of time from either diagnosis or start of treatment that a patient is still alive), as well as progression-free survival in patients who crossed over to receive pimitespib and safety.

Patients across six treatment sites in Japan were enrolled onto the trial from October 2018 to April 2020. The data cut-off date was June 23, 2020. Of the 58 patients who received pimitespib, 50 discontinued treatment due to either progressive disease (39 patients), side effects (4 patients), physician decision (3 patients), withdrawal of consent (2 patients), because they did not take the study drug for more than 21 days (1 patient), or death due to tumor hemorrhage that was unrelated to pimitespib (1 patient).

Of the 28 patients who received treatment with placebo, 17 switched over to treatment with pimitespib. Sixteen discontinued the HSP90 inhibitor because of progressive disease (13 patients), they didn’t take the study drug for more than 21 days (2 patients), or withdrawal of consent (1 patient).

Eight patients are on ongoing treatment with pimitespib compared with four patients who remain on placebo. One patient from the placebo group is still receiving treatment with pimitespib.

Findings showed that the median progression-free survival with pimitespib was 2.8 months compared with 1.4 months with placebo.

Additional data showed that the secondary progression-free survival — in individuals who switched from placebo to study drug — was 2.7 months. No complete or partial responses were reported in either treatment group.

The median overall survival was 13.8 months with pimitespib versus 9.6 months with placebo.

Regarding safety, any severity and serious or severe side effects occurred in 96.6% and 43.1% of patients receiving pimitespib, respectively, and in 78.6% and 28.6% of those on placebo, respectively.

Treatment-related side effects that were any severity or serious or severe occurred in 93.1% and 25.9% of those in the pimitespib group, respectively, and 39.3% and 3.6% of those in the placebo group, respectively. The most common serious or severe treatment-related side effects reported in those who received pimitespib included diarrhea (13.8%), decreased appetite (1.7%), malaise (1.7%), renal impairment (3.4%), and anemia (5.2%).

Side effects that led to dose reductions in the pimitespib and placebo groups occurred in 38.2% and 3.6% of patients, respectively, while side effects that led to dose interruptions were reported in 67.2% and 32.1% of patients, respectively. Moreover, side effects that resulted in study discontinuation occurred in 6.9% and 7.1% of patients on the investigative and control arms, respectively.

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Treatment with the study drug was associated with a doubling of a survival outcome in patients with advanced gastrointestinal stromal tumor, compared to placebo.

Novel Drug Significantly Improves Survival in Advanced Refractory GIST

After six and a half years of follow-up, treatment with Opdivo (nivolumab) alone or in combination with Yervoy (ipilimumab) continued to be associated with long-term survival benefits compared to Yervoy alone in patients with previously untreated advanced melanoma, according to findings presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

The long-term data showed that the median overall survival (time that a patient with cancer is still alive) with the combination of Opdivo and Yervoy was 72.1 months and 36.9 months with Opdivo alone, compared with 19.9 months with Yervoy alone. This is reportedly the longest median overall survival in a phase 3 clinical trial of advanced melanoma.

Additionally, the 6.5-year progression-free survival (time during and after treatment when the patient lives without disease progression) rate was 34% with Opdivo and Yervoy and the median progression free survival was 11.5 months. The rates were 29% and 7% with Opdivo and Yervoy as single agents, respectively; the median progression-free survival was 6.9 months and 2.9 months, respectively.

“The sustained (overall survival) and (progression free survival) benefit shown with (Opdivo)-based treatment, particularly the (Opdivo) plus (Yervoy) combination, has changed the way we look at long-term efficacy outcomes for patients with advanced melanoma,” lead study author Dr. Jedd D. Wolchok, chief of the Immuno-Oncology Service, Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center in New York, stated in a news release. “These new results … with nearly half of patients treated with the (Opdivo) and (Yervoy) combination surviving to 6.5 years, confirm the durable, sustained benefit of the combination in patients with advanced melanoma.”

In 2015, the Food and Drug Administration approved the combination of Opdivo and Yervoy for the treatment of patients with metastatic melanoma, based on earlier findings from CheckMate-067. Opdivo is also approved for use as a single agent in this patient population.

In the double-blind, phase 3 CheckMate-067 study, investigators randomized patients with previously untreated unresectable advanced (stage 3 or 4) melanoma 1:1:1 to receive the combination of Opdivo at 1 mg/kg and Yervoy at 3 mg/kg for four doses, followed by Opdivo at 3 mg/kg every two weeks (314 patients), Opdivo alone at 3 mg/kg every two weeks plus placebo (316 patients), or Yervoy alone at 3 mg/kg every three weeks for four doses plus placebo (315 patients). Treatment was administered until disease progression or unacceptable toxicity.

Assessing progression-free survival and overall survival was the main goal of the study. Additional goals included objective response rate (the rate of a measurable response to the treatment) and safety.

At the 6.5-year analysis, 49% of patients were alive and in follow-up. Of this percentage, 77% of patients who were treated with Opdivo plus Yervoy were reported to be off of therapy and did not receive subsequent systemic treatment. Sixty-nine percent of those on Opdivo alone, and 43% of those on single-agent Yervoy also have been off of treatment and did not require subsequent systemic therapy.

The clinical benefit was sustained and observed with both Opdivo and Yervoy combination and Opdivo alone across relevant subgroups, which included those with BRAF-mutant and BRAF wild-type tumors, and patients with baseline liver metastases.

In patients with BRAF wild-type melanoma, the overall survival rate was 46% in those who received the combination, 42% for Opdivo alone, and 22% for Yervoy alone. In those with liver metastases, the overall survival rates were 38%, 31%, and 22% for the combination, Opdivo monotherapy, and Yervoy monotherapy, respectively.

In the combination group, as well as in the single-agent Opdivo group, the median duration of response (length of time a tumor continues to respond to treatment without the cancer growing or spreading) has still not yet been reached and was 19.2 months for those receiving single-agent Yervoy.

Regarding safety, the profile of Opdivo combined with Yervoy was found to be consistent with prior data of the regimen and no new safety signals were observed. No additional treatment-related deaths had occurred since the five-year analysis of CheckMate-067.

Serious or severe side effects occurred in 59% of patients in the Opdivo and Yervoy combination group, in 24% in the Opdivo group, and in 28% of patients in the Yervoy group.

More than six years of follow-up data show that Opdivo alone, or in combination with Yervoy, continued to induce long-term survival benefits compared to Yervoy alone in patients with previously untreated advanced skin cancer.

Opdivo Alone, or Combined with Yervoy Shows Continued Survival Benefit in Advanced Skin Cancer

Bavencio (avelumab) as front-line maintenance plus best supportive care demonstrated a survival benefit compared with best supportive care alone in patients with advanced urothelial cancer who have progressed on first-line platinum-containing chemotherapy, according to findings from an analysis of a phase 3 trial.

Findings from this analysis were presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

The progression-free survival and overall survival improvements were seen in patients with upper tract or lower tract disease; metastatic disease, unresectable locally advanced disease, or lymph node–only disease; PD-L1–positive tumors who received frontline gemcitabine/carboplatin and tumor genomic subtypes, with the exception of those with the luminal subtype.

Additionally, an analysis of important immune biomarkers by subtype did not predict benefit with Bavencio in the frontline maintenance setting.

“Overall, it doesn’t appear that this molecular … analysis is able to identify the ‘winners and the losers’ associated with maintenance (Bavencio). This is important because it means we need to move to different types of biomarkers in the future,” lead study author Dr. Thomas Powles, a professor of genitourinary oncology and director of Barts Cancer Centre in London, United Kingdom, said in a presentation during the meeting. “We’ve added something to the field today. I believe that biomarker-positive (and) carboplatin subgroups of patients are relevant, and I also think that the molecular analysis builds on what we know and points us in a different direction of biomarker development in the future.”

In the trial, patients with locally advanced or metastatic urothelial cancer that had not progressed on front-line chemotherapy received front-line maintenance with Bavencio plus best supportive care (350 patients) or best supportive care alone (350 patients) until disease progression, unacceptable toxicity or withdrawal from the trial.

Factors that researchers focused on throughout the trial included overall survival in the overall study population and in those with PD-L1–positive tumors, in addition to effects from the treatment based on a patient’s tumor site and type of advanced disease.

The progression-free survival and overall survival benefits were observed irrespective of primary tumor site or type of advanced disease. There was, however, a greater difference of overall survival outcomes in those with lower tract primary tumors, unresectable locally advanced disease or lymph node–only disease following chemotherapy, but the investigators noted that the number of patients and events were small.

The progression-free survival outcomes were similar with Bavencio/best supportive care versus best supportive care alone in these exploratory subgroups: lower tract, locally advanced and unresectable disease and lymph node–only disease. Similar to the overall survival data, the luminal subtype showed the least benefit of the other key immune biomarker subtypes.

In the basal squamous subgroup, the median overall survival was 24 months and 17.9 months with Bavencio/best supportive care (46 patients) and best supportive care alone (44 patients), respectively. In the luminal subgroup, the median overall survival was 23.8 months (30 patients) and not evaluable (26 patients), respectively.

In the luminal-infiltrated group, the median overall survival was 19.9 months with Bavencio/best supportive care (143 patients) and 14.3 months with best supportive care alone (143 patients). Finally, in the luminal papillary subgroup, the median overall survival was 22.5 months with Bavencio/best supportive care (61 patients) compared with 13.4 months with best supportive care alone (63 patients).

Further data showed that longer outcomes were seen in the Bavencio group in patients with PD-L1–positive disease who received front-line gemcitabine/carboplatin for progression-free survival and overall survival. These data were consistent with the overall study population.

Specifically, the median overall survival was 24 months with Bavencio plus best supportive care and 16.1 months with best supportive care alone; the median progression-free survival was 3.7 months and 2.4 months, respectively.

“These data really support further the approach of giving chemotherapy to get control of the disease and then maintaining that control with maintenance (Bavencio) rather than giving front-line immune therapy, in my opinion, and I think this does really add to the field,” Powles said.

The study’s lead author noted that the data support giving patients with advanced bladder cancer chemotherapy to get control of the disease and then maintaining that control with maintenance Bavencio.

Front-line Bavencio Maintenance Improves Survival Regardless of Primary Tumor Site, Advanced Disease Type in Advanced Bladder Cancer

Data from the phase 3 KEYNOTE-564 trial demonstrated that treatment with Keytruda (pembrolizumab) following surgery was associated with a 32% reduction in the risk of disease recurrence or death compared with placebo in patients with clear cell renal cell carcinoma (RCC).

“Adjuvant (Keytruda) following surgery demonstrated a statistically significant and clinically meaningful improvement in (disease-free survival) versus placebo,” lead study author Dr. Toni K. Choueiri, director of the Lank Center for Genitourinary Oncology and director of the Kidney Cancer Center at Dana-Farber Cancer Institute in Boston, said during a presentation of the data prior to the 2021 ASCO Annual Meeting. “KEYNOTE-564 is the first positive phase 3 study of an adjuvant immunotherapy for patients with RCC. (Keytruda) is a potential new standard of care for patients with RCC in the adjuvant setting.”

The standard-of-care treatment for patients with locoregional RCC is surgery; however, nearly half of patients eventually experience disease recurrence. Currently, there is no standard adjuvant (treatment following surgery) systemic therapy that is supported by high levels of evidence worldwide.

In the double-blind, multicenter, phase 3 KEYNOTE-564 study, investigators explored Keytruda versus placebo following nephrectomy (surgical removal of one or both kidneys) in patients with clear cell RCC. Specifically, patients’ disease had to meet criteria that categorized them as high risk for recurrence.

Patients must have undergone nephrectomy within 12 weeks prior to randomization and could not have previously received systemic treatment.

All patients were randomized to receive either 200 milligrams of Keytruda every three weeks or placebo every three weeks, both for approximately one year. Measuring disease-free survival (the time after treatment without signs of cancer) was the main goal of the study. Other goals included assessing overall survival (time that a patient with cancer is still alive) and safety.

At one year, the estimated disease-free survival rates were 85.7% and 76.2% with Keytruda and placebo, respectively. At two years, these rates were 77.3% and 68.1%, respectively.

The overall survival data are immature, with 18 and 33 events occurring in the Keytruda and placebo groups, respectively.

Regarding safety, side effects occurred in 96.3% of patients receiving Keytruda and 91.1% of patients receiving placebo; Serious or severe side effects occurred in 32.4% and 17.7%, respectively. Side effects led to death in two patients in the Keytruda group and in one patient in the placebo group.

Treatment-related side effects occurred in 79.1% and 53.4% of Keytruda- and placebo-treated patients, respectively. A total 18.9% of patients in the Keytruda group experienced serious or severe treatment-related side effects vs 1.2% of those receiving placebo. Of note, no treatment-related side effects led to death in either treatment group. Overall, the safety profile was consistent with prior data regarding Keytruda.

“KEYNOTE-564 is the first phase 3 trial to show improved (disease-free survival) from the addition of an immune checkpoint inhibitor in the adjuvant setting for clear cell RCC, which is the most common type of kidney cancer,” said ASCO’s Executive Vice President Dr. Julie Gralow during the press briefing. “Despite surgery, recurrence is common in clear cell RCC, and if it does recur, there are limited curative treatment options. The results of the KEYNOTE-564 trial support consideration of (Keytruda) as a potential new standard of care in the adjuvant setting to reduce disease recurrence in certain patients with kidney cancer.”

currently approved for use in combination

 with Inlyta (axitinib) for the first-line treatment of patients with advanced RCC.

Treatment with Keytruda following surgery was associated with a significant reduction in the risk of disease recurrence or death compared with placebo in patients with clear cell renal cell carcinoma.

Gina Mauro

Novel Drug Significantly Improves Survival in Advanced Refractory GIST

Opdivo Alone, or Combined with Yervoy Shows Continued Survival Benefit in Advanced Skin Cancer

Front-line Bavencio Maintenance Improves Survival Regardless of Primary Tumor Site, Advanced Disease Type in Advanced Bladder Cancer

Keytruda After Surgery Significantly Improves Survival in Patients with Kidney Cancer

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