Kristi Rosa

Keytruda (pembrolizumab) continued to improve survival versus Yervoy (ipilimumab) in patients with unresectable stage 3 or 4 melanoma, as demonstrated by 10-year follow-up data from the phase 3 study KEYNOTE-006 study presented at the 2024 ESMO Congress.

Eligible patients were able to transition to the open-label phase 3 KEYNOTE-587 extension study, which was designed to continue collecting long-term efficacy in those with solid tumors who received prior Keytruda in a clinical trial. The median time from KEYNOTE-006 entry to KEYNOTE-587 data cutoff was 123.7 months.

A 10-year follow-up data from the KEYNOTE-006 study showed that Keytruda continued to outperform Yervoy in terms of overall survival, progression-free survival, and melanoma-specific survival for patients with advanced melanoma.

Patients who received Keytruda had significantly higher survival rates compared with those who received Yervoy. This includes an overall survival rate of 34% at 10 years for Keytruda compared to 23.6% for Yervoy.

The study found that patients who responded well to Keytruda had excellent long-term outcomes, regardless of their initial disease severity.

Even after patients stopped taking Keytruda, the benefits continued to be evident, with many patients remaining disease-free for extended periods.

For patients whose disease progressed after the first course of Keytruda, a second course demonstrated promising results, with a significant number achieving responses.

Patients who received Keytruda (159 patients) experienced a median overall survival (OS; the time from the start of treatment when a patient with cancer is still alive) of 32.7 months versus 15.9 months with Yervoy (52 patients). The eight- and 10-year OS rates in the Keytruda group were 36.9% and 34%; in the Yervoy group, these rates were 24.8% and 23.6%.

The modified median progression-free survival (PFS; how long a person lives without their disease getting worse) with Keytruda was 9.4 months versus 3.8 months with Yervoy. The PFS rates at eight and 10 years in the Keytruda group were 23.4% and 22%; in the Yervoy group, these respective rates were 12.8% and 12.8%. The median melanoma-specific survival (MSS; how long a patient with melanoma lives) with Keytruda was 51.9 months versus 17.2 months with Yervoy. The eight- and 10-year MSS rates in the Keytruda group were 46.5% and 45.2%; these rates were 32.1% and 31.3% in the Yervoy group.

“With this 10-year follow-up, we have an OS rate of 34% but a MSS rate of 45.2%. We have a very good outcome for patients who responded or who had the benefit to the first course, and again, it shows that response is actually the best marker for long-term outcome. Unfortunately, we cannot know before [treatment] who is going to respond, but the patients who respond really do very well,” Dr. Caroline Robert, of Gustave Roussy and Paris-Saclay University, in Villejuif, France, said in a presentation of the data. “We [also] show that we have an additional activity that is quite significant for patients who are rechallenged if they had the benefit in the first course of [Keytruda]. I also would like to remind you of the safety. We all know that the grade 3 and above [side] effects with a single[-agent] regimen is around 15% to 20%, which is far below what we can see with a combination.”

KEYNOTE-006 enrolled patients with unresectable stage 3 or 4 melanoma not amenable to local therapy who had at least one measurable lesion. Patients were at least 18 years of age, had an ECOG performance status of 0 (fully active) or 1 (limited activity), and known BRAF mutational status. They could have received up to one prior systemic treatment as long as it was not an anti–CTLA-4, PD-1, PD-L1, or PD-L1 agent. Those with uveal or ocular melanoma or with known central nervous system metastases were excluded. Notably, patients with previously treated, stable (neither grows nor shrinks) brain metastases were permitted. Any patients enrolled in this trial who received study treatment or were in the survival follow-up phase of the research were able to transition to the extension study.

In KEYNOTE-006, participants were randomly assigned to receive Keytruda every two weeks up to two years, Keytruda every three weeks up to two years or Yervoy every three weeks for four cycles.

Those who experienced a complete response (CR; when a person's disease cannot be detected by any tests or examinations), which had been confirmed on two scans at least four weeks apart, were able to stop treatment, as long as they received Keytruda for six months or more and had received two or more doses of the agent beyond achievement of CR. Patients who experienced stable disease (SD; the tumor neither grows nor shrinks) or better during the first course of treatment with Keytruda were able to receive a second course every three weeks for up to one year or approximately 17 cycles while in either trial if they experienced progressive disease after discontinuing therapy.

In KEYNOTE-006, investigators evaluated tumor response via CT and MRI scans at week 12; this was subsequently done every six weeks through week 48, and every 12 weeks thereafter. Once treatment was stopped, participants were monitored for survival every 12 weeks until the end of the trial. Those who transitioned to the KEYNOTE-587 study were then followed for long-term survival, progressive disease and initiation of next anti-cancer treatment. Moreover, those who receive a second course of Keytruda in the extension trial were also followed for assessment.

The primary focus of this trial was OS. Exploratory areas of interest included PFS and PFS on the second course of Keytruda. Investigators conducted analyses that examined MSS in the overall population, OS in subsets, OS and modified PFS from week 94 in those who received at least 94 weeks of Keytruda, and more.

Of those assigned to Keytruda treatment in KEYNOTE-006 (556 patients), 228 were eligible to transition to KEYNOTE-587, and 159 were enrolled in the trial. Of the 278 patients assigned to the Yervoy group on KEYNOTE-006, 105 were able to enroll in the extension trial and 52 did so.

Keytruda continued to show superiority over Yervoy with regard to OS outcomes across all subgroups analyzed, including those with elevated lactate dehydrogenase levels (indication of tissue damage and some types of cancer; 270 patients), those with large tumors defined as at least 10 centimeters (186 patients) and those with brain metastases (80 patients).

In those who completed at least 94 weeks of treatment with Keytruda (103 patients), and with a median follow-up duration of 122.9 months, the median OS from week 94 was not reached (meaning half of the patients in the study were alive at the time researchers assessed this); the six- and eight-year OS rates from week 94 were 91.8% and 80%, respectively. The median modified PFS in those who completed 94 weeks or more of Keytruda was also not reached (meaning that half of the patients in the study had not experienced disease progression at the time data were analyzed); the six- and eight-year modified PFS rates from week 94 were 73.2% and 64.8%, respectively.

Of the patients who received a second course of Keytruda in either trial (16 patients), five achieved a CR, five experienced a partial response (decrease in tumor size or extent of cancer), four had SD, and two experienced disease progression. The median modified PFS from the start of the second course of Keytruda was 51.8 months; four- and six-year modified PFS rates from the start of the second course were 56.3% and 49.2%, respectively.

Of the overall population (556 patients), 66.2% of those who received Keytruda and 65.1% of those given Yervoy received the agents in the first-line setting. In these patients, the median OS with Keytruda or Yervoy was 38.7 months and 17.2 months. The respective 8-year OS rates were 40.1% and 27%; the 10-year OS rates were 36.9% and 25%. The median modified PFS in these patients who received Keytruda or Yervoy as first-line treatment was 12 months and 4.1 months. The eight- and 10-year modified PFS rates were 27% and 25.5% with Keytruda and 15.1% and 15.1% with Yervoy.

“These results confirm that Keytruda provides long-term benefit in patients with advanced melanoma, supporting it as a standard of care in this setting,” the study authors conclude.

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Articles

Keytruda continued to improve survival versus Yervoy in unresectable stage 3 or 4 melanoma in long-term follow-up data.

Long-Term Study Data Support Keytruda as Standard of Care for Advanced Melanoma

Patients with muscle-invasive bladder cancer who are not eligible or refuse to receive presurgical gemcitabine chemotherapy demonstrated responses to TAR-200 with cetrelimab, findings from a phase 2 study showed, as presented at the 

TAR-200 is a type of drug delivery system that helps sustain the release of gemcitabine chemotherapy into the bladder, according to Johnson & Johnson.

Cetrelimab is a type of monoclonal antibody which binds certain targets in the body to help the immune system destroy cancer cells, as the National Cancer Institute defines.

Patients with muscle-invasive bladder cancer who were ineligible or refused presurgical gemcitabine chemotherapy showed positive responses to a combination of TAR-200 and cetrelimab.

Treatment with TAR-200 plus cetrelimab led to higher rates of pathologic complete response (pCR) and pathologic overall response compared to cetrelimab alone.

The achievement of pCR in patients who received presurgical chemotherapy has been linked to lower risk of death and recurrence.

In the phase 2 SunRISe-4 study, a total of 122 patients with muscle-invasive bladder cancer who were scheduled for radical cystectomy (surgical removal of the bladder) and were ineligible for or refused presurgical chemotherapy were randomly assigned to two groups.

The first group included 79 patients who were treated with TAR-200, gemcitabine chemotherapy and cetrelimab. The second group included 41 patients who received cetrelimab alone. A total of 53 patients in the TAR-200 combination group and 31 patients in the cetrelimab alone group were determined evaluable for efficacy.

“SunRISe-4 demonstrates for the first time a benefit of the addition of TAR-200, an intravesical targeted releasing system, to checkpoint inhibition as presurgical treatment in patients with MIBC,” Dr. Andrea Necchi of IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, in Milan, Italy, said in a late-breaking oral presentation of the data.

Treatment with TAR-200 plus cetrelimab in 53 patients led to a pathologic complete response (pCR; complete disappearance of cancer) rate of 42% and a pathologic overall response (pOR; percentage of patients whose cancer shrunk or disappeared) rate of 60% in the efficacy-evaluable population of patients with cT2 to cT4a disease. Treatment of cetrelimab alone in 31 patients, which was also evaluated, led to respective pCR and pOR rates of 23% and 36%.

For patients with MIBC who have T2 to T4a N0M0 disease, the standard-of-care treatment approach is to undergo radical cystectomy with or without presurgical cisplatin-based chemotherapy (such as gemcitabine), but up to half of patients are eligible for chemotherapy. Approximately 50% of patients who undergo radical cystectomy will have their cancer return within two years. After the procedure, the five-year survival rates are still low, at about 50%, Necchi said.

“Also, in patients with MIBC undergoing radical cystectomy, we know that pathological stage is prognostic (the likelihood) for survival,” he added. With the procedure alone, pCR rates range from 10% to 15%; with presurgical chemotherapy, the pCR rate rose to approximately 30%; and with presurgical checkpoint inhibition, the pCR rates fell between 31% and 39%.

The achievement of pCR in patients who have received presurgical chemotherapy has been linked with a 55% lower risk of death and an 81% lower recurrence risk versus those who have residual disease. “There is a high unmet need for more tolerable treatment options for patients with MIBC who are candidates for radical cystectomy, but not candidates for or who refuse presurgical chemotherapy,” Necchi underscored.

Phase 1 data have demonstrated TAR-200’s clinical activity in patients with muscle-invasive bladder cancer.

The main goal of the trial was pCR, and secondary goals included recurrence-free survival (living without the cancer returning) and safety. Exploratory goals included pOR, overall survival (time patients live, regardless of their disease status), time to symptomatic progression, quality of life and biomarker analysis.

Necchi said that the main baseline characteristics between the groups were “pretty well balanced.” Regarding presurgical chemotherapy, 39.2% of those in the combination group were ineligible and 60.8% refused it, and in the cetrelimab alone group, these respective rates were 36.6% and 63.4%. In the combination group, 20.3% of patients had visible residual disease before starting therapy, and this was also true for 14.6% of those in the cetrelimab alone group. Regarding tumor stage in the combination group, 78.5% had cT2 disease and 21.5% had cT3-cT4a disease; these rates were 85.4% and 14.6%, respectively, in the cetrelimab alone group. Further, 20.3% and 26.8% of patients had urothelial carcinoma with variant histology. “There are [also] a few patients with a history of intravesical therapy, in general meaning, a history of previous non-muscle-invasive disease progressing to muscle-invasive disease,” Necchi said.

Regarding safety, at least one treatment-related side effect of any severity was experienced by 72.2% of those in the combination group and 43.9% of those in the cetrelimab alone group. The most common treatment-related side effects in these respective groups were dysuria (painful or uncomfortable urination; 27.8%; 18.3%), pollakiuria (frequent urination; 27.8%; 18.3%), micturition urgency (sudden and strong urge for urination; 15.2%; 10%) and hematuria (blood in urine; 13.9%; 9.2%).

Treatment-related side effects that were grade 3 (severe) or worse were reported in 11.4% of those in the combination group and 4.9% of those in the cetrelimab alone group. Serious treatment-related side effects occurred in 11.4% of those in the combination group and 2.4% of those in the cetrelimab alone group. Treatment-related side effects led to discontinuation of TAR-200 in 8.9% of patients and cetrelimab discontinuation in 7.6% of patients — all in the combination group. One patient in the cetrelimab alone group experienced a treatment-related side effect that proved fatal.

Grade 3 or worse immune-related toxicities were experienced by 6.3% of those in the combination group and 4.9% of those in cetrelimab alone group. The median time to radical cystectomy in the respective groups was 13.7 weeks and 12.6 weeks.

Patients with muscle-invasive bladder cancer who were treated with presurgical chemotherapy may have a 55% lower risk of death, research shows.

Presurgical Cetrelimab With TAR-200 Shows Responses in Muscle-Invasive Bladder Cancer

A new study shows that Keytruda combined with chemoradiotherapy can significantly improve survival for patients with advanced cervical cancer.

Keytruda (pembrolizumab) plus chemoradiotherapy, followed by Keytruda monotherapy, significantly improved survival versus chemoradiotherapy alone in newly diagnosed, previously untreated, high-risk locally advanced cervical cancer, according to updated data from the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study presented during a press briefing of the 2024 ESMO Congress.

The data, which were simultaneously published in 

, showed that at a median follow-up of 29.9 months, the 36-month overall survival (OS; the time when a patient with cancer is still alive) rate was 82.6% with Keytruda plus chemoradiotherapy versus 74.8% with chemoradiotherapy alone. The median OS was not reached (NR) in either arm, meaning that at least half of patients in the study are still alive at the time the data were analyzed.

Keytruda plus chemoradiotherapy significantly improved overall survival compared to chemoradiotherapy alone in patients with high-risk locally advanced cervical cancer.

The risk of death was reduced by 33% in patients receiving Keytruda plus chemoradiotherapy.

Keytruda plus chemoradiotherapy had a manageable safety profile, with no new safety signals observed.

Patients treated with Keytruda plus chemoradiotherapy had a significantly longer time before disease progression compared to those receiving chemoradiotherapy alone.

The benefits of Keytruda plus chemoradiotherapy were observed across various patient subgroups, including those with different stages of disease and PD-L1 expression levels.

“When we add [Keytruda], the risk of death is reduced by 33%, and it is really remarkable for this tumor, which is among the worst among the gynecological malignancies; it involves younger patients,” Dr. Domenica Lorusso, of the Gynaecology/Oncology Unit of Fondazione Policinico Universitario A. Gemelli IRCCS, Rome and Humanitas San Pio X, in Milan Italy, said in a press briefing at the congress where she initially shared some of the data. “It is a really painful tumor for women. In the locally advanced setting, it is our only opportunity to cure a larger number of patients, and [Keytruda] is able to do it.”

The phase 3 study enrolled patients 18 years of age or older with newly diagnosed, locally advanced squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma of the cervix. Patients needed to have high-risk disease. Patients were required to have an ECOG performance status of 0 or 1 (fully active or restricted in usual activities), acceptable organ function and available tissue for sampling.

They were randomly assigned to receive [Keytruda] plus chemoradiotherapy followed by [Keytruda] or placebo plus chemoradiotherapy followed by placebo.

The primary endpoints of the trial were progression-free survival (PFS; the time during and after treatment when a patient with cancer is alive without disease worsening) and OS. Secondary endpoints included 24-month PFS, 36-month OS, objective response rate (the percentage of patients with a complete or partial response to treatment), duration of response, patient-reported outcomes and safety.

A total of 1,060 patients were randomly assigned at 176 clinical sites spanning 30 countries. A total of 529 patients were allocated to the Keytruda/chemoradiotherapy arm, and they comprised the intention-to-treat (ITT)/efficacy population; 528 were treated, and they represented the as-treated/safety population. At the time of data cutoff, 16.3% remained on treatment, 41.5% completed treatment and 42.2% discontinued; the main reason for discontinuation in this group was radiographic progression (108 patients).

A total of 531 patients were allocated to the placebo/chemoradiotherapy arm, and they comprised the ITT/efficacy population; 530 were treated and they represented the as-treated/safety population. At cutoff, 16% remained on treatment, 39.4% completed treatment and 44.5% discontinued; radiographic progression was also the most common reason for discontinuation in this group (158 patients).

“More than 95% of patients had PD-L1–positive tumors [defined as having a] combined positive score of 1 [or higher],” Lorusso said. “Fifty-six percent of patients had stage 3 and 4A [disease], 85% had positive lymph nodes, and in particular, 62% in the pelvis and [about] 20% in the pelvic and para-aortic area.”

With regard to treatment exposure, the median number of Keytruda or placebo cycles in the respective arms was 17 and 16. The median number of cisplatin cycles in both arms was 5. Overall treatment time for radiotherapy in the Keytruda and placebo arms was 52 days. In the Keytruda arm, radiotherapy was completed within 50 days for 35.5% of patients and within 56 days for 74.2% of patients. “This is remarkable considering it is a global trial in 146 patients during the [COVID-19] pandemic,” Lorusso noted. In the placebo arm, these respective rates were 36.8% and 74.7%. The median duration of external beam radiation therapy and brachytherapy was 37 days and 12 days, respectively, in both arms.

PFS data were shared at the time of the first analysis, which had a median follow-up of 17.9 months. The 24-month PFS rate with Keytruda plus chemoradiotherapy was 67.8% versus 57.3% with chemoradiotherapy alone. The median PFS was NR in both arms, meaning that at least half of patients had not experienced disease progression or death at the time data were analyzed; the 30% reduction in the risk of disease progression was determined to be of statistical significance.

“Considering that the PFS endpoint [met] successful criteria at the first interim analysis, we did not [formally] analyze at the second interim analysis,” she added. With a median follow-up of 29.9 months, the 36-month PFS rate in the [Keytruda] arm was 69.3% versus 56.9% in the placebo arm. The median PFS was still NR in both arms.

Keytruda plus chemoradiotherapy had a manageable safety profile. “We were surprised of the good tolerability of [Keytruda] in combination with chemoradiation,” she said. “There were no new safety signals.” With longer follow-up, 78.2% of those in the Keytruda arm and 70% of those in the placebo arm experienced grade 3 (severe) or higher all-cause side effects; grade 3 or higher treatment-related side effects occurred in 69.1% and 61.3% of patients, respectively. All-cause serious side effects were experienced by 32.6% of those in the Keytruda arm versus 28.5% of those in the placebo arm; they were treatment related in 19.3% and 13.4% of patients, respectively. Any treatment discontinuation due to side effects was reported in 20.6% and 14.9% of patients in the respective arms. “Of note, only one patient in the [Keytruda] arm discontinued all treatment for a non–[Keytruda]-related AE,” Lorusso said.

The most common treatment-related side effects experienced by 20% or more patients in the Keytruda and placebo arms, respectively, were anemia (60.0% versus 55.8%), nausea (57.6% versus 59.8%), diarrhea (50.8% versus 51.1%), decreased white blood count (32.8% versus 34.5%), decreased neutrophil count (low level of a type of white blood cell that helps the body against infections; 29.5% versus 27.9%), vomiting (25.6% versus 28.3%), leukopenia (decreased number of a type of white blood cell that helps the body against infections; 23.7% versus 17.4%), decreased platelet count (blood cells that help your blood to clot, and low levels may lead to your body taking longer to stop bleeding; 22% versus 20.6%), neutropenia (low levels of neutrophils in the body; 21.6% versus 17.7%) and hypothyroidism (when the thyroid gland does not produce enough thyroid hormone; 21.2% versus 5.7%).

“We pay particular attention to diarrhea because of a possible overlapping toxicity between autoimmune-related colitis and post-radiotherapy colitis. However, no signals [were observed],” Lorusso noted.

The most common immune-mediated side effects experienced by three or more patients in the Keytruda or placebo arms were hypothyroidism (22.5% versus 6.8%), hyperthyroidism (when they thyroid gland produces too much thyroid hormone) 12.1% versus 2.8%), gastritis (inflammation of the lining of the stomach; 4.2% versus 3.8%), colitis (inflammation of the colon; 3% versus 2.1%), thyroiditis (inflammation of the thyroid gland; 2.3%; 0.4%), pneumonitis (inflammation of the lungs; 1.9% versus 0.9%), severe skin reactions (1.3% versus 0.9%), adrenal insufficiency (when the adrenal glands do not produce enough cortisol, which helps the body respond to stress; 0.8% versus 0%), nephritis (inflammation of the kidneys; 0.6% versus 0.2%), and pancreatitis (inflammation of the pancreas; 0.6% versus 0.2%).

Patients with previously untreated, high-risk locally advanced cervical cancer experienced improved survival when treated with Keytruda plus chemoradiotherapy.

Keytruda Plus Chemoradiotherapy May Represent New Standard of Care in Cervical Cancer Subset

A new study reveals Enhertu effectively treats breast cancer that has spread to the brain, offering hope for patients with this challenging condition.

Considerable and durable overall and intracranial activity occurred with Enhertu (T-DXd; fam-trastuzumab deruxtecan-nxki) in patients with HER2-positive metastatic breast cancer with stable and active brain metastases (cancer that spreads from the primary location to the brain), as demonstrated in findings from the phase 3b/4 DESTINY-Breast12 study presented at the 

In the cohort of patients with baseline brain metastases (263 patients), the primary end point was progression-free survival (PFS; the time during and after treatment when a patient with cancer lives with the disease without worsening). The 12-month PFS rate was 61.6% and the median PFS was 17.3 months. The 12-month PFS rates with the agent were consistent in those with stable (remaining the same size; 157 patients) and active (increasing in size; 106 patients) brain metastases, at 62.9% and 59.6%. Within the group of patients with active brain metastases, a slightly lower 12-month PFS rate was observed in those with previously untreated disease (39 patients), with a rate of 47%; those with previously treated disease (67 patients) had a 12-month PFS rate of 66.7%.

The study found that Enhertu significantly improved progression-free survival (PFS) and overall response rate (ORR) in patients with HER2-positive metastatic breast cancer, both with and without brain metastases.

Enhertu showed comparable efficacy in patients with stable and active brain metastases, suggesting its potential benefits for a wide range of patients.

While the study identified some common side effects, the overall safety profile of Enhertu was generally consistent with previous reports, and no new safety signals were identified.

ILD/pneumonitis continues to be an important safety risk, especially in patients with brain metastases receiving concomitant steroids. Careful monitoring and preventive measures are necessary.

The primary end point was overall response rate (ORR; the percentage of patients with a partial or complete response to treatment) in the cohort of patients without brain metastases at baseline. In this group (241 patients), the confirmed ORR was 62.7% and this was comprised of a complete response (disappearance of all signs of cancer from treatment; CR) rate of 9.5% and a partial response (PR; decrease in tumor size) rate of 53.1%. In those with measurable disease at baseline (215 patients), the ORR with the agent was 68.4%, which included CR and PR rates of 9.3% and 59.1%, respectively. Dr. Nancy U. Lin, of the Department of Medical Oncology at Dana-Farber Cancer Institute, noted in an oral presentation that the ORR was in line with previous trials that have examined Enhertu in this setting.

“Overall, we believe that results from DESTINY-Breast12 support the use of [Enhertu] for patients with HER2-positive metastatic breast cancer, irrespective of the presence or absence of stable or active brain metastases,” Lin said. “The safety profile of [Enhertu] was consistent with previous reports, and no new safety signals were identified. Interstitial lung disease [thickening or scarring of the tissue within lungs; ILD]/pneumonitis (inflammation of the lungs) remains an important identified safety risk of [Enhertu], and in particular, in patients with brain metastases on concomitant steroids. Careful attention to PCP prophylaxis (preventive treatment to prevent a type of lung infection) and workup for opportunistic infections is warranted.”

About half of patients with HER2-positive metastatic brain cancer go on to develop brain metastases, Lin said. Although Tukysa (tucatinib)-based regimens have shown efficacy, the median PFS with this regimen in those with brain metastases who were 

 was under eight months, she added. As such, there is a need for additional effective therapeutic options for this population.

 for adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received an anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of therapy completion. The full approval was based on 

findings from the phase 3 DESTINY-Breast03 trial

The phase 3b/4 DESTINY-Breast12 study enrolled patients with HER2-positive advanced or metastatic breast cancer with or without brain metastases at the start of the study. These patients had received up to two prior lines of treatment in the metastatic setting, not including Tukysa, and experienced progressive disease on previous HER2-directed regimens. To be included, they were required to be at least 18 years of age and have an ECOG performance status of 0 or 1 (fully active or limited in strenuous activity). They could not have known or suspected leptomeningeal metastases (when cancer cells spread from the original location to the meninges, thin layers of tissue that protect the brain and spinal cord).

Patients were divided into two cohorts: those with baseline brain metastases and those without. Those with brain metastases at baseline were divided further in those with stable brain metastases that were previously treated and those with active brain metastases which were untreated or previously treated and progressing but not requiring immediate local therapy. Those in both cohorts received Enhertu every three weeks.

For those with baseline brain metastases, in addition to PFS serving as the primary end point, other end points included central nervous system (CNS) PFS, overall survival (the time when a patient with cancer is still alive; OS), ORR, CNS ORR, safety and tolerability. For those without brain metastases at baseline, in addition to ORR serving as the primary end point, other end points included OS, safety and tolerability.

Taking a Closer Look at the Patient Populations

Of the 263 patients who comprised the baseline brain metastases group, 157 had stable metastases and 106 had active metastases. Of those with active metastases, 39 were untreated and 67 were previously treated and progressing. Of this full group with baseline brain metastases, 55.1% discontinued treatment with Enhertu, the most common reason being progressive disease (30.8%). The median follow-up duration was 15.4 months, and 44.9% of patients were still on treatment at data cutoff.

Of the 241 patients without brain metastases at baseline, 60.6% discontinued treatment with the antibody-drug conjugate (ADC); the most common reason for doing so was also progressive disease (35.7%). The median follow-up duration in this group was 16.1 months, and 39.4% of patients were still on the agent at data cutoff.

Additional data from the cohort of patients with baseline brain metastases showed that the 12-month CNS PFS rate was 58.9% at a data maturity rate of 38.4%. Broken down further, the CNS PFS rates in those with stable and active brain metastases were 57.8% and 60.1%, respectively. The confirmed ORR in the full population of patients with baseline brain metastases was 51.7%; in those with stable and active metastases, these rates were 49.7% and 54.7%, respectively. When restricted to patients with measurable disease at baseline, the ORR in the full group of baseline brain metastases (198 patients) was 64.1%; in those with stable (109 patients) and active (89 patients) brain metastases, these rates were 67.0% and 60.7%, respectively.

A total of 138 patients were enrolled with measurable CNS disease at baseline. In this group, the confirmed CNS ORR was 71.7%. In those with stable metastases (77 patients), the confirmed CNS ORR was 79.2%; in those with active metastases (61 patients), this rate was 62.3%. Within those with active brain metastases, the confirmed CNS ORRs in the subgroups of patients with untreated (23 patients) or previously treated and progressing (38 patients) metastases were 82.6% and 50%, respectively.

The 12-month OS rates in those with or without brain metastases at baseline were 90.3% and 90.6%, respectively, at data maturity of 16.3% and 17%, respectively. “The median OS was not reached,” Lin noted. When OS is not reached in a trial, this means that at the time of analysis, more than half of patients in the study were still alive.

Regarding safety, in the baseline brain metastases group (263 patients), 98.5% of patients experienced any-grade side effects; these effects were grade 3 (severe) or higher for 51% of patients. Serious side effects occurred in 23.6% of patients. Any-grade, grade 3 or higher, and serious side effects determined to potentially be related to the ADC occurred in 92%, 38%, and 9.5% of patients, respectively. Side effects required dose reductions and interruptions in 22.8% and 55.5% of patients, respectively; side effects led to discontinuation for 15.2% of patients. Eight patients experienced side effects that led to death, with six determined to possibly be related to Enhertu.

In the group of patients without brain metastases at baseline (241 patients), 98.3% of patients experienced any-grade side effects, 49.0% experienced grade 3 or higher side effects, and 19.1% experienced serious side effects; these effects were possibly related to the ADC in 95.4%, 40.7%, and 10.4% of patients, respectively. Side effects led to dose reduction or interruption for 27% and 51.5% of patients, and discontinuation for 9.5% of patients. Six patients experienced side effects that proved fatal and five were possibly related to Enhertu.

“The toxicity profiles were qualitatively similar regardless of the presence or absence of brain metastases,” Lin said. “The most common all-grade toxicities were nausea, fatigue and constipation. No new safety signals were identified.”

Lin also reported on side effects of special interest with Enhertu. In patients with baseline brain metastases, investigator-reported ILD or pneumonitis occurred in 16% of patients; this effect was grade 1 (mild) for 9.9% of patients, grade 2 (moderate) for 3% of patients, grade 3 for 0.4% of patients and grade 4 (life threatening) for 0.4% of patients. In those without baseline brain metastases, 12.9% experienced investigator-reported ILD or pneumonitis; patients experienced grade 1 (9.1%), 2 (2.5%), 5 (1.2%) cases. A decrease in left ventricular ejection fraction (when the heart’s left ventricle pumping less blood than it should) occurred in 11.8% of those with baseline brain metastases (grade 2, 11.0%; grade 3, 0.8%) and 10.8% without baseline brain metastases (grade 1, 1.7%; grade 2, 9.1%).

Patients with HER2-positive breast cancer benefitted from treatment with Enhertu regardless of brain metastasis. 

Kristi Rosa

Long-Term Study Data Support Keytruda as Standard of Care for Advanced Melanoma

Presurgical Cetrelimab With TAR-200 Shows Responses in Muscle-Invasive Bladder Cancer

Keytruda Plus Chemoradiotherapy May Represent New Standard of Care in Cervical Cancer Subset

Enhertu Demonstrates Overall, Intracranial Activity in HER2-Positive Breast Cancer

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