 Will Pizii 

Higher doses of tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR) T-cell therapy, displayed better survival rates at 1 year for young patients compared with patients who received lower doses who have B-cell lymphoblastic leukemia (B-ALL). Doses remained within the FDA-approved dosing range.

“In the past, we did not have data to guide clinical decisions around commercial CAR T-cell dosing and didn’t know if higher doses would affect toxicity and compromise outcomes, or support enhanced anti-leukemia effect,” said Liora Schultz, MD, pediatric oncologist at the Stanford Children's Health, Lucile Packard Children's Hospital, and the study’s lead author. “This data has direct clinical applicability, as it supports use of higher dosing, as available, within the approved tisagenlecleucel dose range.”

ALL has been found to be the most common type of childhood cancer, with B-ALL being the most common subtype of the disease. Chemotherapy often suffices to treat B-ALL, but approximately 20% of patients either do not respond to chemotherapy or relapse after. In response, CAR T-cell therapy is growing to become a pivotal component for standard of care as an alternate or supplement therapy to stem cell transplantation for young patients with relapsed or refractory B-ALL

For patients weighing 50 kg or less, the approved dosing range is 0.2 to 5 × 10

 CAR T cells/kg. For patients weighing over 50 kg, the approved dosing range is 10 to 250 × 10

 CAR T cells/kg. CAR T cell numbers vary for each patient considerably, based on the number of CAR T cells obtained initially and at what rate the modified cells grow in the laboratory.

Investigators analyzed 185 patients aged 26 or younger who received tisagenlecleucel for relapsed or refractory B-ALL for overall survival, event-free survival, and relapse-free survival after 1 year. Patients receiving the higher dose range (2.4-5.1 × 10

 cells/kg) had higher survival rates across those 3 end points vs patients who received treatment at the lower dose range (0-1.3 × 10

 cells/kg). Eighty-six percent of patients in the higher dose group were alive at the end of 1 year vs 59% who were still alive in the low dose group. Investigators did not find any evidence of increased toxicity or safety concerns with the higher treatment dose range.

Such results suggest higher doses of tisagenlecleucel can achieve more effective response without increased toxicity risk.

“A lot of effort is focused on complex engineering and development of next-generation CAR-T therapies,” said Schultz. “This study aims to explore if clinical manipulations using our current approved construct, tisagenlecleucel, can achieve even incremental advances in the field.”

Further research will be planned to examine the data and analyze additional clinical variables, which may influence results after CAR T-cell therapy.

Higher doses of CAR-T therapy bring survival advantage for young patients with hard-to-treat B-ALL. Press release. American Society of Hematology; August 8, 2022. Accessed August 10, 2022. https://bit.ly/3Pe4jV7

Articles

Tisagenlecleucel boosted survival rates in children with B-cell lymphoblastic leukemia. Further research will be planned to examine the data and analyze additional clinical variables.

CAR T-Cell Treatment at Higher Doses Reveal Beneficial Survival Data Without Worry of Added Toxicity

A phase 1b clinical trial testing devimistat (CPI-613) in combination with gemcitabine and cisplatin indicated for patients with locally advanced unresectable or metastatic biliary tract cancer has been successfully completed.


This multicenter trial (NCT04203160) enrolled 20 patients in its phase 1b segment and found the gemcitabine, cisplatin, devimistat combination to be well tolerated. The overall response rate was 45%, and the median progression-free survival (PFS) was 14.9 months. Seven patients are still in treatment. The median overall survival (OS) is not estimable after a median follow-up of 11.5 months.


The randomized phase 2 portion of the trial is now open and collecting patients from 10 cancer centers across the US, with a target enrollment of 78 patients.


“We are very pleased with the results of the trial, as we advance to phase 2,” said Sanjeev Luther, president, and CEO of Cornerstone Pharmaceuticals. “Advanced biliary tract cancer is a rare and aggressive form of cancer with a 5-year survival rate of less than 5%. The continuation of the trial aligns with our mission to provide hope to patients and loved ones affected by biliary tract cancer and other rare cancers.”


“With strong and continued trial enrollment rates, the research community remains engaged in identifying the capabilities devimistat has in biliary cancer,” said Vaibhav Sahai, MD, MBBS, MS, principal investigator of the trial and medical oncologist at the University of Michigan Rogel Cancer Center in Ann Arbor, Michigan. “Devimistat is a potentially life-saving therapy, and we remain optimistic in its promise as the study continues to yield positive results, giving us great hope for the future of biliary cancer care.”


Devimistat targets enzymes involved in cancer cell energy metabolism, located in the mitochondria. This treatment is aimed to target the mitochondrial tricarboxylic acid cycle in cancer cells. The FDA gave devimistat an orphan drug designation for the treatment of pancreatic cancer, acute myeloid leukemia, myelodysplastic syndrome, peripheral T-cell lymphoma, soft tissue sarcoma, Burkitt’s lymphoma, and biliary tract cancer.


The phase 1 primary outcome of the study is the incidence of dose-limiting toxicity which will determine the recommended phase 2 dosage. The secondary end points are PFS, OS, and incidence of toxicities.


Eligible patients must have a pathologically or cytologically confirmed carcinoma of the biliary tract that is not eligible for curative resection, transplantation, or ablative therapies. Patients with tumors of mixed cholangiocarcinoma/hepatocellular carcinoma histology are excluded. Patients must also have radiographically measurable disease in at least 1 site not previously treated with radiation or liver-directed therapy, be of at least 18 years of age, and have an ECOG performance score of 0 or 1.


Patients are excluded from the study if they have prior history of brain metastasis or organ transplant, underwent a major surgical procedure less than 4 weeks before enrollment, active second malignancy other than in situ cancer or localized prostate cancer, active heart disease including symptomatic heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia or interstitial lung disease, or known hypersensitivity to cisplatin, gemcitabine, or CPI-613, or its inactive components.


1. Cornerstone pharmaceuticals announces successful completion of phase 1b clinical trial for CPI-613® (devimistat) in combination with gemcitabine and cisplatin in patients with biliary tract cancer. Press release. Yahoo Finance; August 3, 2022. Accessed August 8, 2022. https://yhoo.it/3JEEr3F

2. Gemcitabine and cisplatin with or without CPI-613 as first line therapy for patients with advanced unresectable biliary tract cancer (BilT-04). ClinicalTrials.gov. Updated May 25, 2022. Accessed August 8, 2022. https://bit.ly/3bE3Spj

A study of devimistat in combination with gemcitabine and cisplatin indicated for patients with locally advanced unresectable or metastatic biliary tract cancer has been successfully completed.

Early Study of Devimistat/Gemcitabine in Biliary Cancer Concludes

The addition of tremelimumab to durvalumab (Imfinzi) and chemotherapy improved clinical benefit and survival benefit in patients with PD-L1 negative metastatic non–small cell lung cancer (mNSCLC), according to results from the phase 3 POSEIDON study (NCT03164616) presented at the 2022 World Lung Cancer Conference in Vienna, Austria.

Median overall survival (OS) favored the tremelimumab plus durvalumab and chemotherapy group, and OS benefit was greater in patients who received durvalumab plus chemotherapy in the patient group with tumor cells (TC) of at least 1%, according to lead author Edward B. Garon, MD, MS, professor of medicine, Geffen School of Medicine at the University of California Los Angeles.

The median OS for patients with PD-L1 TC of 1% or greater was 15.6 months (95% CI, 11.6-18.1) with the couplet plus chemotherapy, 14.4 months (95% CI, 11.8-17.5) with durvalumab plus chemotherapy, and 12.6 months (95% CI, 10.4-15.2) in the chemotherapy-alone group. Median OS for patients with PD-L1 less than 1% were 12.7 months (95% CI, 9.9-15.5) for the tremelimumab plus durvalumab and chemotherapy group, 10.9 months (95% CI, 8.1-13.5) for durvalumab plus chemotherapy, and 11.0 months (95% CI, 8.7-12.7) with chemotherapy alone.

Patients with mNSCLC (N = 1013) were randomized 1:1:1 to receive 75 mg of tremelimumab plus 1500 mg of durvalumab plus chemotherapy once every 3 weeks for 4 cycles, 1500 mg of durvalumab plus chemotherapy once every 3 weeks for 4 cycles, or chemotherapy once every 3 weeks up to 6 cycles. End points included OS, progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety in subgroups with PD-L1 status of 1% or greater and less than 1% as well as across different histology types.

The median PFS for patients with PD-L1 (TC) of 1% or greater was 6.2 months (95% CI, 5.0-6.6) with tremelimumab, durvalumab, and chemotherapy, 6.4 months (95% CI, 4.9-6.7) with durvalumab and chemotherapy, and 4.9 months (95% CI, 4.9-6.0) with chemotherapy alone. The median PFS for patients with PD-L1 TC less than 1% was 6.1 months (95% CI, 4.6-6.5), 4.6 months (95% CI, 4.0-5.0), and 4.7 months (95% CI, 4.6-6.2), respectively.

Patients with non-squamous disease with PD-L1 TC of 1% or greater had median OS of 22.1 months (95% CI, 15.9-27.8) with the doublet and chemotherapy, 17.1 months (95% CI, 13.3-23.9) with durvalumab plus chemotherapy, and 13.5 months (95% CI, 10.6-18.8) with chemotherapy alone. Patients with non-squamous disease with PD-L1 TC of less than 1% had a median OS of 13.4 months (95% CI, 9.8-18.7), 11.7 months (95% CI, 7.5-17.0), and 12.3 months (95% CI, 9.3-14.1), respectively.

Patients with squamous disease and PD-L1 TC of 1% or greater had a median OS of 9.8 months (95% CI, 7.6-12.5) with tremelimumab plus durvalumab plus chemotherapy, 12.3 months (95% CI, 9.5-15.7) with durvalumab plus chemotherapy, and 10.6 months (95% CI, 9,0-15.2) with chemotherapy alone. These same patients but with PD-L1 TC less than 1% had median OS of 12.7 months (95% CI, 7.7-14.1), 9.8 months (95% CI, 7.4-13.5), and 8.8 months (95% CI, 4.8-11.8), respectively.

In patients with PD-L1 TC expression 1% or greater, those who received the triplet combination had an ORR of 40.0%. Patients who received the doublet combination had an ORR of 49.1% and those who received chemotherapy alone had an ORR of 27.6%.

The median DOR heavily favored the doublet plus chemotherapy group with PD-L1 TC of 1% or greater. The median DOR in this group was 16.4 months (95% CI, 7.2-nonestimable), and the median DOR for durvalumab plus chemotherapy was 7.2 months (95% CI, 5.6-12.7), and 5.1 months (95% CI, 4.2-5.4) with chemotherapy alone. Median DOR for patients with PD-L1 TC less than 1% were 7.8 months (95% CI, 5.1-12.5), 6.7 months (95% CI, 3.8-9.0), and 5.5 months (95% CI, 3.7-12.7), respectively.

Treatment-related adverse events (AEs) and grade 3 and 4 AEs were similar among the treatment types within their respective patient subgroups and consistent across the whole population.

These results suggest adding tremelimumab to durvalumab and chemotherapy as a treatment option for patients with low or PD-L1 negative mNSCLC.

Garon EB, Cho BC, Luft A, et al. Durvalumab (d) ± tremelimumab (t) + chemotherapy (ct) in 1l metastatic nsclc: outcomes by tumour pd-l1 expression in POSEIDON. E-Poster presented at the 2022 World Lung Cancer Conference; August 6-9, 2022; Vienna, Austria. Accessed August 4, 2022. 

Tremelimumab plus durvalumab and chemotherapy displayed improvements in clinical and survival benefit in patients with PD-L1 negative metastatic non–small cell lung cancer.

Triplet Combo Conveys Survival Benefit in PD-L1-Positive mNSCLC

A clinical trial collaboration and supply agreement (CTCSA) between Erasca, Inc and Eli Lilly and Company will evaluate the anti-EGFR antibody cetuximab (Erbitux), supporting the ongoing phase 1/1b FLAGSHP-1 trial (NCT04670679) examining ERAS-601, an oral SHP2 inhibitor in combinations, including for the treatment of triple wild-type (

 wild-type) metastatic colorectal cancer (CRC) and human papillomavirus (HPV)-negative advanced head and neck squamous cell carcinoma (HNSCC).

Erasca previously signed CTCSAs with Lilly and Pfizer to evaluate cetuximab and encorafenib (Braftovi) in combination with Erasca’s ERK1/2 inhibitor, ERAS-007, as part the HERKULES-3 phase 1b/2 trial (NCT05039177). Erasca is the sponsor of this trial, and Lilly will supply cetuximab at no cost.

“We are pleased to enter another clinical trial collaboration with Lilly to explore cetuximab in combination with ERAS-601, our SHP2 inhibitor, in 

-driven cancers that are highly dependent on RAS/MAPK signaling,” said Jonathan E. Lim, MD, chairman, chief executive officer, and co-founder of Erasca, in a press release. “Dual inhibition of EGFR and SHP2, a convergent RTK signaling node, has the potential to broaden and deepen responses relative to cetuximab monotherapy and delay onset of resistance in cancers like triple wildtype metastatic CRC and HPV-negative advanced HNSCC.”

The FLAGSHIP-1 trial is an open-label, multicenter clinical study of ERAS-601 as a monotherapy and in combination with other therapies. The trial consists of 4 parts. Part A is a dose-escalation where patients will receive oral ERAS-601 monotherapy, part B is a dose-escalation where patients with receive ERAS-601 in combination with intravenous cetuximab, part C is dose-expansion with ERAS-601 monotherapy based off part A, and part D is a dose-expansion with ERAS-601 and cetuximab combination based off part B. Investigators will measure dose-limiting toxicities, maximum tolerated dose, recommended dose, adverse events, plasma concentration (Cmax), and time to Cmax. Secondary end points include objective response rate, duration of response, and time to response.

To be included in the study, patients must be at least 18 years of age, have a histologically or cytologically confirmed advanced or metastatic solid tumor, and had no standard systemic therapy for the tumor histology and/or molecular biomarker profile. Patients must also be able to swallow oral medication, have an ECOG performance score of 0 or 1, have adequate cardiovascular, hematological, liver, and renal function.

Patients with previous treatment with a SHP2 inhibitor, documented 

 mutations, or are currently receiving another study therapy or have participated in a study of an investigational agent and received study therapy within 4 weeks of the first dose of ERAS-601 will be ineligible for participation. Other exclusionary criteria include those who have received prior palliative radiation within 7 days of cycle 1, day 1, have primary central nervous system (CNS) disease or known active CNS metastases and/or carcinomatous meningitis, have had prior surgery or gastrointestinal dysfunction that may affect drug absorption, have clinically significant interstitial lung disease or pneumonitis, a history of thromboembolic or cerebrovascular events within 12 weeks prior to the first dose of study treatment, or a history or current evidence of retinal vein occlusion.

Erasca announces clinical trial collaboration and supply agreement with eli lilly and company to evaluate ERAS-601 and cetuximab combination. Press release. Yahoo Finance; July 18, 2022. Accessed August 5, 2022. 

Erasca has entered into a clinical trial collaboration and supply agreement with Eli Lilly and Company to evaluate the anti-EGFR antibody cetuximab.

ERASCA and Eli Lilly Collaborate to Investigate ERAS-601 and Cetuximab Combination 

The FDA has granted approval to acalabrutinib’s (Calquence) new tablet formulation for all current indications, including adult patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and for relapsed or refractory mantle cell lymphoma (MCL).

This approval decision was made based on the results of the ELEVATE-PLUS trials, which were presented at the 63rd American Society of Hematology Annual Meeting & Exposition in December 2021.

Results from ELEVATE-PLUS showed the acalabrutinib capsule and tablet formulations are bioequivalent, indicating that both have the same efficacy and safety profile with the same dosing strength and schedule. It is noted that the tablet can be taken with gastric acid-reducing agents, including proton pump inhibitors (PPIs), antacids, and H2-receptor antagonists. Adverse events and safety were mild in these studies and no new safety signals were identified.

“Patients with blood cancers like chronic lymphocytic leukemia and mantle cell lymphoma are often older and may face multiple medical conditions that may need intervention, including acid reflux or peptic ulcer disease. The US approval of acalabrutinib in a tablet form enables co-administration of the acalabrutinib tablet alongside a proton pump inhibitor. This provides another option for some patients with chronic lymphocytic leukemia and relapsed or refractory mantle cell lymphoma, enabling more patients to potentially benefit from this treatment,” said John C. Byrd, MD, chair of the Department of Internal Medicine at the University of Cincinnati, in the press release. 

The ELEVATE-PLUS trials consist of 3 phase 1, open-label, single-dose, cross-over studies conducted in 116 patients. The trials established bioequivalence between 100 mg acalabrutinib tablets and 100 mg acalabrutinib capsules, evaluated the PPI effect of acalabrutinib tablets administered in the presence vs the absence of PPI rabeprazole (Aciphex), and investigated the effect of food by comparing acalabrutinib tablets administered with a high-fat diet vs a fasted diet.

The acalabrutinib capsule formulation is also approved for the same indications as the tablet in the United States and other nations.

Acalabrutinib is a next-generation, selective inhibitor of bruton’s tyrosine kinase (BTK) which binds covalently to BTK, inhibiting its activity. In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.

“Today’s approval of the new Calquence tablet formulation will offer physicians and patients increased flexibility when devising treatment plans for chronic lymphocytic leukemia and mantle cell lymphoma. This new option is a result of our focus on understanding the wants and needs of this community and providing patient-focused solutions for their treatment,” said Dave Fredrickson, executive vice president of the Oncology Business Unit at AstraZeneca, in the press release.

Kemp A. Calquence tablet formulation approved in the US across current indications. Press release. AstraZeneca; August 5, 2022. Accessed August 5, 2022. 

Acalabrutinib’s new tablet formulation has been granted FDA approval for all current indications, including adult patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, and relapsed or refractory mantle cell lymphoma.

FDA Approves New Tablet Form for Acalabrutinib 

Though number of United States residents insured through Medicaid has increased significantly over previous years, barriers to accessing cancer care still exist at high-quality centers, according to data published in the 

Researchers at the Yale Cancer Center assessed the acceptance of Medicaid insurance among patients diagnosed with colorectal, breast, kidney, and skin cancer to find that insurance acceptance varied across treatment centers.

“We found that Medicaid acceptance differed widely across cancer care facilities, with a substantial number of centers not offering services to patients with Medicaid insurance,” said Michael Leapman, MD, MHS, associate professor of urology, clinical program leader for the Prostate & Urologic Cancers Program at Yale Cancer Center and Smilow Cancer Hospital, and senior author on the study, in a press release.

Of the 334 Commission on Cancer-accredited facilities, 226 (67.7%) accepted new patients with Medicaid insurance for the 4 cancer types analyzed. The facilities had varying acceptance rates according to the cancer types, including 296 (88.6%) which accepted Medicaid for at least 3 of the disease types, 324 (97.0%) that accepted for at least 2 types, and 331 (99.1%) that accepted at least 1 type.

These findings highlight the inconsistencies among Medicaid catered services at cancer care centers. Hospital-level Medicaid acceptance included 302 facilities (90.4%) accepting colorectal, 319 facilities (95.5%) accepting breast, 290 (86.8%) for kidney, and 266 (79.6%) for skin cancer.

“This study underscores that having health insurance alone does not necessarily mean that patients can practically access healthcare. While major recent expansions of Medicaid have led to increases in health insurance coverage for Americans with cancer, we have to be aware and do more to ensure that insurance will actually translate to timely and high-quality care,” added Leapman.

High access to patients with Medicaid coverage were more likely accepted at National Cancer Institute-designated cancer centers (89.7%), academic centers (86.4%), followed by community centers (74.7%), integrated network facilities (69.4%), and comprehensive community cancer programs (54.0%). High access acceptance was less likely observed at for-profit hospitals (42.1%) than nongovernment, nonprofit (69.6%) and government facilities (79.5%). Researchers also noted that facilities in the US who expanded Medicaid were more likely to offer high access to Medicaid patients compared to states who did not expand Medicaid (71.3% vs 59.6%, respectively).

“The results of this study do not necessarily mean that patients will not be able to access care anywhere, but may require a circuitous and impractical path, and may not be seen at centers designated for cancer care,” Leapman said. “Despite a large increase in the number of Medicaid-insured patients, most factors that limit a hospital or physician’s participation in Medicaid have not changed. These include low reimbursement, high administrative burden, and limited specialist participation in managed care organization networks. Even modest increases in reimbursement may have a positive impact, and progress in payment structures that prioritize healthcare quality are promising as well. Still, identifying these gaps in access is an important first step that can direct awareness.”

The study concluded that facilities with integrated salary models had greater access for patients with Medicaid. Physicians within integrated systems were more willing to see patients with Medicaid when compensation is based on salary or work-relative value regardless of patient insurance status.

1. Marks VA, Hsiang WR, Nie J, et al. Acceptance of simulated adult patients with medicaid insurance seeking care in a cancer hospital for a new cancer diagnosis. 

. 2022;5(7):e2222214. Published 2022 Jul 1. doi:10.1001/jamanetworkopen.2022.22214

2. For medicaid-insured patients with cancer, health insurance does not always mean health access. Press release. Yale School of Medicine. July 15, 2022. Accessed August 4, 2022. https://bit.ly/3bsCXge

Disparities exist for Medicaid-insured patients at centers designated for high-quality care, according to researchers from Yale Cancer Center. 