Jason Harris

Patients with relapsed/refractory multiple myeloma benefited from treatment with MCARH109, a CAR-T cell therapy targeting the “enigmatic” GPRC5D antigen which generated remissions in 70.6% of patients, according to data from a first-in-human phase 1 trial.

Twelve of 17 patients experienced a measurable decline in their cancer after receiving MCARH109 CAR-T cells. Six patients (35%) achieved complete response and 10 patients (59%) had very good partial response or better. Eight patients (47%) had minimal residual disease negativity in bone marrow.

Although the study population was small, co-author Dr. Renier Brentjens, the Katherine Anne Gioia Endowed Chair in Cancer Medicine, chair of the department of medicine and deputy director at Roswell Park Comprehensive Cancer Center, said these findings open a new plan of attack for treating multiple myeloma.

“What’s scientifically exciting is that we now have two populations of targeted cells which we think we can now feasibly treat patients with concomitantly, potentially and that is very exciting,” Brentjens explained in an interview. “That will certainly help set a proof of principle for other malignancies that we will target with CAR-T cells, including solid tumor malignancies. It really is a significant step forward in the field. It’s still to be seen how meaningful this is —whether it’s an opportunity to prolong responses … or to potentially enhance responses. We’re very excited about that part of it.”

Physicians have achieved deep, durable responses using B-cell maturation antigen (BCMA)–targeting CAR T-cell therapies in patients with multiple myeloma. However, data from some studies show that progression-free survival is less than 12 months, an indicator of myeloma recurrence despite the persistence of CAR-T cells. Relapse is common and mechanisms of resistance are not fully defined, although recent data suggests that the identification of BCMA expression, copy number variation and point mutations appeared to be key indicators of resistance for patients receiving BCMA-targeting CAR-T cell therapy or T-cell engagers.

Investigators at Roswell Park developed MCARH109 in partnership with Memorial Sloan Kettering Cancer Center (MSKCC) and Dana-Farber Cancer Institute. Brentjens said investigators began exploring cellular therapeutic targets for multiple myeloma about 10 years ago. They identified three targets including BCMA, which is now FDA approved in the form of drugs, such as Carvykti (ciltacabtagene autoleucel) and the antigen GPRC5D.

“GPRC5D is an intriguing target because it’s really nicely upregulated on multiple myeloma cells, but not expressed in most normal tissues, with some exceptions in the skin, for example,” he explained. “We knew even back then that we were likely going to have to go after more than on target.”

Duration is limited for BCMA-directed therapy and there are few treatment options for patients who relapse. In preclinical models, investigators found in vitro and in vivo antitumor efficacy with GPRC5D CAR-T cells in multiple myeloma, including in a BCMA antigen escape model. GPRC5D is highly expressed in myeloma cell lines and in bone marrow plasma cells of patients with multiple myeloma. The antigen is found less often in plasma cells in normal tissue and has low expression in a subset of cells in the hair follicles and hard keratinizing tissue.

The 17 patients in the phase 1 trial, conducted at MSKCC, had undergone a median of six prior treatments for myeloma, including CAR-T cell therapy targeting BCMA, proteasome inhibitors, immunomodulatory agents (IMiDs) and anti-CD38 antibody–based therapies. Eligible patients had an ECOG score of zero or one and adequate organ function. Baseline GPRC5D expression in the bone marrow was not required for enrollment.

Patients could receive bridging therapy following apheresis but had to discontinue at least two weeks before initiating lymphodepleting chemotherapy. Lymphodepletion consisted of daily 300 mg/m2 cyclophosphamide plus 30 mg/m2 fludarabine for three consecutive days. Two days after the completion of lymphodepletion, investigators administered MCARH109 at four dose levels.

Investigators followed all patients until disease progression. Long-term follow-up continued until death or withdrawal of consent.

The median patient age was 60. All patients received previous treatment with two proteasome inhibitors, two IMiDs and one anti-CD38 antibody. Sixteen patients (94%) had triple-refractory disease.

Ten patients (59%) had received previous treatment with BCMA-targeted therapies, including eight (47%) who received previous BCMA CAR-T cell therapy. Nine responded to BCMA-targeted therapy and two were refractory to the treatment. The median time from last BCMA therapy to MCARH109 infusion was 16.4 months.

All patients had previously received high dose melphalan and undergone an autologous stem cell transplantation. Three patients (18%) had previously received allogeneic transplantation.

Fourteen patients (82%) were refractory to their last line of therapy. Sixteen patients (94%) received bridging therapy after leukapheresis and 15 were refractory to bridging therapy.

Three patients (18%) had nonsecretory myeloma at baseline and eight (47%) had extramedullary plasmacytoma. Thirteen (76%) had one or more high-risk cytogenetic features.

At a median follow-up of 10.1 months, six of 12 patients (50%) with a partial response or better remained progression free. Two patients completed more than one year of follow-up after MCARH109 infusion.

The median duration of response (DOR) was 7.8 in the entire cohort. The median DOR was also 7.8 months in patients who received CAR-T cells.

At the maximum tolerated dose of CAR-T cells, 58% of patients had a response.

Seven of 10 patients who received previous BCMA-targeted therapies had partial response or better. The same was true for three of six patients (50%) treated at 25 × 106 to 150 × 106 doses of CAR-T cells.

Fourteen patients experienced grade 1/2 cytokine release syndrome (CRS). One patient at the highest dose level had a grade 4 CRS event. Investigators said this patient had grade 4 immune effector cell–associated neurotoxicity syndrome (ICANS) and grade 4 macrophage activation syndrome, which constituted a dose-limiting toxic effect. No other patients had ICANS or macrophage activation syndrome.

Two other patients at the highest dose level experienced a grade 3 cerebellar disorder that investigators determined was possibly related to MCARH109 and constituted a dose-limiting toxic effect for this dose.

The most common grade 3 or higher side effects included neutropenia (94%), thrombocytopenia (65%) and anemia (35%). Nonhematologic grade 3 or higher events were uncommon.

Three patients (18%) experienced infections. Two experienced grade 3 events (bacterial infection and parvovirus infection, respectively).

Twelve patients were treated at dose levels that did not produce unacceptable side effects. Seven of those (58%) had an objective response.

“They had relapsed or been refractory to BCMA-targeted CAR-T cells, and yet we are still able to demonstrate clinical meaningfully clinical responses using the GPRC5D CAR-T cells,” Brentjens said. “We now actually have two targets for patients with multiple myeloma rather than just one. We can start to potentially explore (targeting two) different antigens on the multiple myeloma tumor cell, either sequentially or concurrently, which is really exciting to potentially utilize this dual targeted approach to get more durable and long-term remissions in patients.

“To the best of my knowledge, this the first time that we really have identified two targets on one tumor cell, both of which demonstrate really promising and significant responses. That really begs the question of, if we put the two populations together, will there be a synergistic benefit when assessing durability of response?”

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A new T-cell therapy showed benefits in patients with relapsed/refractory multiple myeloma.

New T-Cell Therapy Shows Improved Response in Resistant Multiple Myeloma

A tumor test reliably determined which premenopausal patients with HR-positive breast cancer would benefit by adding ovarian function suppression to their presurgical endocrine therapy, and which patients can skip ovarian suppression, which can come with short- and long-term side effects.

The Breast Cancer Index test showed that younger women with certain characteristics tended to benefit more from ovarian function suppression, according to findings from the SOFT trial, which were presented at the 2022 San Antonio Breast Cancer Symposium.

“This is the first genomic assay to demonstrate benefit from ovarian suppression, supporting additional clinical utility and value and validation of (Breast Cancer Index) and premenopausal women,” Dr. Ruth O’Regan, chair of medicine and Charles A. Dewey Professor at the University of Rochester, said in a presentation of the findings.

Younger Women Benefit More From Ovarian Suppression

The SOFT trial included 3,066 premenopausal women with HR-positive breast cancer. Patients were split up into three groups and randomly assigned to receive tamoxifen alone; tamoxifen plus ovarian function suppression; or exemestane plus ovarian function suppression, all for five years.

Data from that trial showed a 3% improvement in 12-year freedom from distant recurrence with exemestane plus ovarian function suppression compared with tamoxifen alone.

However, ovarian suppression can be toxic, and patients can struggle to continue taking the drugs. Therefore, it is crucial to identify which patients are most likely to benefit, O’Regan said.

Data from SOFT showed that women younger than 35 years appear to derive benefit from ovarian function suppression following chemotherapy.

Furthermore, investigators have developed a system that incorporates risk value age, nodal status, tumor size, grade, estrogen receptor (ER) status, progesterone receptor status, and Ki-67 that can assist with estimating the individual risk-based benefit of escalating endocrine therapy for HER2-negative patients.

“However, today, no genomic biomarker has been available to predict the benefit of errands of ovarian suppression premenopausal patients,” O’Regan said. “This is critical because of not just the short-term toxicities, but also long-term toxicities, which may not already be fully established.”

Seeking a Biomarker for Ovarian Suppression Benefit

To develop such a biomarker, O’Regan and her colleagues evaluated the predictive and prognostic ability of the Breast Cancer Index test in 1,711 patient tumor samples collected from the SOFT trial.

“(Breast Cancer Index) has been found to be prognostic in determining individualized risk of late recurrences and also cumulative overall distant recurrence from year zero to year 10,” O’Regan said.

The tool analyzes the ratio of two genes — HOXB13 and IL187BR, known as the (H/I) status —which previous studies showed can lend insight into the prognosis of patients with certain types of breast cancer.

The main goal of this study was to determine whether Breast Cancer Index (H/I) status was predictive for benefit with exemestane plus ovarian function suppression compared to tamoxifen. Investigators hypothesized that Breast Cancer Index (H/I)-high status would be predictive for ovarian suppression benefit, while BCI (H/I) low status would not.

In the data presented at SABCS, investigators assessed tumor samples collected from 573 patients assigned to tamoxifen, 551 assigned to tamoxifen plus ovarian suppression and 563 assigned to exemestane. The average follow-up was 12 years.

In the Breast Cancer Index analysis group of 1,687 patients, half (50.1%) of patients had grade 2 tumors, 25.4% had grade 1, 22.9% had grade 3, and tumor grade was unknown in 1.5%.

Patient age ranged from younger than 35 years (11.3%) to older than 50 years (10.6%). More than 65% of patients had no disease in their lymph nodes; 25.3% had disease in one to three of their lymph nodes; and 9.0% had disease in four or more lymph nodes. Tumor size was equal to or less than 2 cm in 64.1% of patients, greater than 2 cm in 34.4%, and was unknown in 1.5%.

For HER2 status, 11.7% of patients were positive. Most patients (53.3%) received chemotherapy. O’Regan said the Breast Cancer Index analysis cohort was representative of the parent SOFT trial.

Investigators determined that 58% of cancers were BCI (H/I) low and 42% were BCI (H/I) high. There was a significant treatment by biomarker interaction for exemestane plus ovarian function suppression compared to tamoxifen. The interaction was not as strong for tamoxifen plus ovarian suppression compared to tamoxifen alone.

In the overall HR-positive cohort, those with (H/I)-high tumors, patients did not derive an absolute benefit for exemestane plus ovarian function suppression compared to or tamoxifen plus ovarian function suppression versus tamoxifen.

In contrast, investigators observed an absolute benefit of 11.6% for exemestane plus ovarian function suppression versus tamoxifen in the (H/I)-low group. For tamoxifen plus ovarian suppression versus tamoxifen, the absolute benefit was 7.3%.

In patients with HR-positive, HER2-negative tumors, BCI (H/I) was again predictive in the low group. The absolute 12-year benefit was 13.2% for exemestane plus ovarian suppression versus tamoxifen and 7.4% for tamoxifen plus ovarian function suppression versus tamoxifen.

In the BCI (H/I) group, the absolute benefit was –0.2% for exemestane plus ovarian function suppression compared to tamoxifen and –6.8% for tamoxifen plus ovarian function suppression versus tamoxifen.

Investigators also found that predictive performance was generally consistent across subgroups, including nodal status, prior chemotherapy, and age. Furthermore, consistent with data reported from the SOFT trial, the benefit derived from tamoxifen plus ovarian function suppression was smaller than the benefit derived from exemestane plus ovarian function suppression.

“BCI risk scores were prognostic in premenopausal women with HR-positive tumors receiving adjuvant endocrine therapy (with or without) chemotherapy in that higher BCI risk scores were associated with the worse outcome,” O’Regan said. “The BCI (H/I) was predictive of ovarian suppression benefit. However, contrary to our study hypothesis, the BCI (H/I)-low group consistently derived clinically meaningful benefit while the BCI (H/I)-high group did not. We’re not sure what these results mean, but it does point to potential differences in tumor biology underlying the ovarian suppression response.”

Recent research sought to determine which patients with HR-positive breast cancer can benefit by adding ovarian function suppression to their adjuvant regimens, and which patients can skip it. 

Tumor Test May Predict Which Patients With HR-Positive Breast Cancer Will Benefit From Ovarian Suppression 

Treatment with HER3-DXd (patritumab deruxtecan) was associated with inducing encouraging responses in patients with HER3-expressing metastatic breast cancer or metastatic triple-negative breast cancer.

Data presented at the 2022 American Society of Clinical Oncology Annual Meeting demonstrated that the novel drug, an HER3 directed antibody drug conjugate, elicited an objective response rate (percentage of patients whose disease partially or fully responds to treatment) of 30.1% at a median follow-up of 31.9 months. Of note, treatment with HER3-DXd only resulted in partial responses.

The median duration of response (or time a disease responds to treatment without getting worse) in this cohort was 7.2 months. The median progression-free survival (time a patient lives without disease progression) was 7.4 months and the median overall survival (time a patient is alive regardless of disease progression) was 14.6 months.

In patients with HER3-high metastatic triple-negative breast cancer, the objective response rate was 22.6%. Again, all responses to treatment were partial. The median duration of response to treatment in this group was 5.9 months, with a median progression-free survival of 5.5 months and a median overall survival of 14.6 months.

In patients with HER3-high, HER2-positive metastatic breast cancer, the objective response rate was 42.9%. All responses were partial. The median duration of response was 8.3 months, with a median progression-free survival of 11 months and median overall survival of 19.5 months.

“Significant unmet need still remains for the treatment of patients with metastatic breast cancer and new treatment strategies need to be continuously explored,” lead study author Dr. Ian E. Krop, chief clinical research officer and associate cancer center director for clinical research at Yale Cancer Center in New Haven, Connecticut, said in a press release announcing the findings. “Results from this trial show that (HER3-DXd) produces clinically meaningful and durable antitumor activity in patients and further study is warranted to further evaluate the efficacy and safety of this HER3-directed (antibody drug conjugate) across patients with HR-positive/HER2-negative, HER2-positive, and (triple-negative breast cancer).”

An analysis of 113 patients with HER3-high or HER3-low, HR-positive/HER2-negative metastatic breast cancer, 53 patients with HER3-high triple-negative breast cancer and 14 patients with HER3-high, HER2-positive metastatic breast cancer was conducted.

Assessing the safety and efficacy of treatment with HER3-DXd was the main goal of the study.

A median of six prior lines of therapy had been administered in the advanced setting to patients with HR-positive/HER2-negative disease before study enrollment. Those with metastatic triple-negative breast cancer received a median of two prior therapies. As for patients with HER2-positive metastatic breast cancer, they received a median of 5.5 prior therapies.

A pooled safety analysis of all 182 patients was conducted. Treatment-emergent side effects led 9.9% of the patients in the study to discontinue treatment.

Treatment-related severe or worse side effects were reported in 120 patients. Some of the side effects included, but were not limited to, decreased appetite, nausea, fatigue, diarrhea and vomiting.

Twelve patients developed treatment-related interstitial lung disease or pneumonitis, which is inflammation of the lungs.

At a follow-up of more than two years, treatment with a novel drug produced meaningful results in a group of patients with HER3-expressing metastatic breast cancer or metastatic triple-negative breast cancer.

Early Study Findings Show Novel Drug Elicits Promising Results in Metastatic Breast Cancers

Children with high-risk neuroblastoma — a type of cancer that typically affects young children — who are being treated on a clinical trial tend to have poorer outcomes if they are non-white Hispanic or on public insurance, according to an analysis of data from multiple Children’s Oncology Group (COG) trials. 

Lead author Dr. Puja J. Umaretiya, a clinical fellow in pediatric hematology/oncology at Dana-Farber Cancer Institute and Boston Children's Hospital, in Massachusetts, presented the findings at a press briefing ahead of the 

. She said that the results suggest that equal access to care does not necessarily translate into equitable outcomes.

“Our data show that Hispanic children with high-risk neuroblastoma have inferior overall survival compared with other children,” she said. “This is despite having access to the same clinical trials and receiving the same uniform plan treatment and after controlling for disease associated factors.

“We acknowledge that describing disparities is simply not enough, we must strive to identify mechanisms that cause inequitable outcomes,” she said. “And in this cohort, we begin to do so by looking at things like stopping a trial, early delays in therapy, or increased rates of relapse, none of which seem to explain the survival differences that we see by race and ethnicity.”

In the study analysis, average five-year overall survival was approximately 47% for Hispanic children compared with 50% for other non-Hispanic children, 61% for white non-Hispanic children, and 63% for Black non-Hispanic children.

Umaretiya said that existing data have shown that Black children with neuroblastoma are more likely to experience late relapse. Furthermore, children with public insurance, a proxy for household poverty, are more likely to relapse and more likely to die when treated on immunotherapy trials.

The causes for these disparities are unknown. Investigators felt that a clinical trial was the ideal setting to explore the question because care is highly standardized. They sought to identify the associations between survival and race, ethnicity and socioeconomic status. Investigators also wanted to explore associations between those factors and possible mechanisms for poorer survival like early trial discontinuation, delays in induction chemotherapy and relapsed disease.

Umaretiya and her team conducted a retrospective cohort study on data from 699 children with high-risk neuroblastoma treated in three upfront COG trials from 2007 to 2016: ANBL0532, evaluating two high-dose chemotherapy regimens followed by a stem cell transplant; ANBL0P1, evaluating induction therapy followed by meta-iodobenzylguanidine labeled with iodine-131 and chemotherapy in treating patients undergoing stem cell transplant, radiation therapy and maintenance therapy with isotretinoin; and ANBL12P1 evaluating busulfan, melphalan and stem cell transplant following chemotherapy.

Five-year overall survival was lower among children who used only public insurance compared to others (53% vs 63%) and among children living in neighborhood level poverty compared to others (54% vs 62%). However, Umaretiya added that proxy poverty measures did not remain significantly associated with survival after adjusting for other factors including race, ethnicity and disease-associated factors.

“We looked at mean duration of induction by days and found that overall, by race and ethnicity, there were no significant differences. We also found that there was no difference in who stopped trial participation early by race and ethnicity,” she said. “A little over one-third of patients stopped the trial early, regardless of racial or ethnic group. We also found that there were no differences in the frequency of relapse by race and ethnicity, and that about half of patients relapse, regardless of race or ethnicity.”

Umaretiya and her team also observed no difference in overall survival rural vs urban areas.

Investigators will next examine the interaction of survival and race, ethnicity and poverty, acknowledging the intersectionality of these factors due to structural racism in the United States.

“Our data also suggests that even though we relapse occurs at the same frequency across racial and ethnic groups, the rates of death do not,” Umaretiya said. “Our next steps will focus on this post-relapse period and (we will) specifically look at enrollment on early-phase trials as a proxy for access to life extending therapy as well as the causes of death, looking at whether these children die of disease or toxicity.”

ASCO President Dr. Everett E. Vokes, chair of the department of medicine at the University of Chicago said that children in these trials should have had similar outcomes and that they did not raises important questions.

“We see discrepancies here in overall survival … of 8% to 10% at the longer terms of follow up,” he said. “They seem to correlate with socioeconomic factors and race, but the specific causes of death, or increased death, in those groups are not elucidated yet. And I think that that will be important work moving forward.”

Research showed that Hispanic children with neuroblastoma who are participating on clinical trials tended to have worse survival outcomes than others. 

Jason Harris

New T-Cell Therapy Shows Improved Response in Resistant Multiple Myeloma

Tumor Test May Predict Which Patients With HR-Positive Breast Cancer Will Benefit From Ovarian Suppression

Early Study Findings Show Novel Drug Elicits Promising Results in Metastatic Breast Cancers

Hispanic Children With Neuroblastoma Have Poorer Trial Outcomes: Describing Disparities Is ‘Simply Not Enough’

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