Phase 1/2 findings highlight the utility of adagrasib monotherapy for patients with previously treated 

G12C–mutated non–small cell lung cancer (NSCLC), according to results from cohort A of the phase 1/2 KRYSTAL-1 trial (NCT03785249). The results, which were presented at the 

2022 American Society of Clinical Oncology (ASCO) Annual Meeting

, showed that the drug was responsible for promising objective response and disease control rates (DCR), as well as overall survival (OS).

At the meeting, Alexander I. Spira, MD, PhD, FACP, codirector of Virginia Cancer Specialists Research Institute, director of the Thoracic and Phase I Program, and clinical assistant professor at Johns Hopkins School of Medicine, presented data as of October 15, 2021, from the registrational phase 2 cohort A study, which was simultaneously published in the 

After a median follow-up of 12.9 months, the objective response rate (ORR) was 43% (95% CI, 33.5%-52.6%) among the 112 patients with measurable disease at baseline, which included 1 complete response (CR; 1%) and 47 partial responses (PRs; 42%). There were 41 patients with stable disease (SD; 37%) and 6 with progressive disease (5%) for a DCR of 80% (n = 89; 95% CI, 70.8%-86.5%). There were no differences in ORR by subgroup in exploratory analyses.

“Responses appear to be deep, with 75% of responders having a greater than 50% tumor reduction,” Spira said.

Moreover, the median time to response with the KRASG12C inhibitor was 1.4 months (range, 0.9-7.2) and median duration of response was 8.5 months (95% CI, 6.2-13.8).

Spira noted that as of the data cut-off, treatment is ongoing in half of patients who experienced a response (n = 24) and 33% (n = 16) have maintained their response.

Lastly, the median progression-free survival (PFS) was 6.5 months (95% CI, 4.7 to 8.4), with 6- and 12-month PFS rates of 52% and 29%, respectively. Similarly, the median OS was 12.6 months (95% CI, 9.2-19.2), with 6- and 12-month OS rates of 71% (95% CI, 61.1-78.3) and 51% (95% CI, 40.9-60.0), respectively.

The investigators further evaluated efficacy among 33 patients with treated, stable central nervous system (CNS) metastases. The intracranial ORR was 33% (n = 11; 95% CI, 18%-52%), which included 5 CRs (15%) and 6 PRs (18%). There were 17 patients with SD (52%) for a DCR of 85% (n = 28; 95% CI, 68%-95%). The median intracranial PFS was 5.4 months (95% CI, 3.3-11.6).

Treatment-related adverse events (TRAEs) of any grade occurred in 113 patients (97%), of which 50 (43%) were grade 3/4 in severity. The most frequent any-grade TRAEs were diarrhea (63%), nausea (62%), vomiting (47%), fatigue (41%), ALT increase (28%), blood creatinine increase (26%), AST increase (25%), and decreased appetite (24%). Two grade 5 events occurred: cardiac failure and pulmonary hemorrhage.

TRAEs led to dose reductions in 60 patients (52%), interruptions in 71 (61%), and discontinuation in 8 (7%).

Commenting on the presentation, Sukhmani Kaur Padda, MD, of the Samuel Oschin Cancer Center at Cedars-Sinai Medical Center, noted: “I am curious about a lower optimal starting dose. We talk about this all the time as it relates to targeted therapy… Co-mutations may help further delineate sequencing of therapeutics in 

Adagrasib, formerly MRTX849, is a covalent inhibitor that irreversibly and selectively binds KRAS G12C. “We know that 

G12C mutations act as oncogenic drivers and occur in about 14% of patients with NSCLC, predominantly adenocarcinoma,” Spira explained. “About 27% to 42% of these patients will have CNS metastases at diagnosis. Adagrasib…was optimized for desired properties of a KRASG12C inhibitor, including a long half-life, [approximately] 23 hours, dose-dependent pharmacokinetics, and CNS penetration.”

In the first-in-human trial of the agent, 15 patients with 

G12C–mutated NSCLC demonstrated an ORR of 53.3%, a median DOR of 16.4 months, and a median PFS of 11.1 months. “As previously reported, clinical activity with adagrasib has been shown in various 

G12C–mutated solid tumors, including of course NSCLC, colorectal, pancreatic, ovarian, endometrial, and other [gastrointestinal] GI cancers,” Spira said.

Therefore, in the multicohort KRYSTAL-1 trial, investigators are assessing adagrasib as monotherapy or in combination with other therapies in patients with advanced solid tumors harboring a 

In the registrational phase 2 cohort A study, 116 patients with NSCLC previously treated with platinum-based chemotherapy and anti–PD-1/L1 therapy received 600 mg oral adagrasib twice daily. Investigators aimed to evaluate ORR, DCR, PFS, OS, and safety.

Key eligibility criteria included patients with NSCLC who harbored a 

G12C mutation, unresectable or metastatic disease, and prior treatment with a PD-1/L1 inhibitor in combination or in sequence with chemotherapy. Those with treated, stable CNS metastases were allowed on the trial.

Median age was 64 years (range, 15-89). Most patients were women (56%), White (84%), had an ECOG status of 1 (84%), were former smokers (86%), and had received prior platinum-based therapy and checkpoint inhibitor therapy (98%).

“Based on these data, the [new drug application] for adagrasib has been accepted and is under review for accelerated approval in the US, and the [marketing authorization applications] has been recently submitted to the European Medicines Agency,” Spira said, adding that the phase 3 KRYSTAL-12 trial (NCT04685135), designed to evaluate adagrasib monotherapy vs docetaxel in previously treated patients with 

Spira AI, Riely GJ, Gadgeel SM, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation. 

. 2022;40(suppl 16):9002 doi:10.1200/JCO.2022.40.16_suppl.9002

Jänne PA, Riely G, Gadgee SM, et al. Adagrasib in non–small-cell lung cancer harboring a 

. Published online June 3, 2022. doi:10.1056/NEJMoa2204619

Articles

Investigators reported an objective response rate of 43% and a disease control rate of 80% among patients with previously treated KRAS G12C–mutated non–small cell lung cancer who received the KRAS G12C inhibitor adagrasib.

Adagrasib Associated With Promising Disease Control Rate in KRAS G12C–Mutant NSCLC

The addition of nimotuzumab to gemcitabine reduced the risk of death by 50% compared with gemcitabine alone in a subset of patients with 

 wild-type advanced pancreatic cancer and demonstrated significant improvements in overall survival (OS) rates, according to results from the phase 3 NOTABLE trial (NCT02395016) presented at the 

The median OS was 10.9 months vs 8.5 months for the investigative combination vs placebo, respectively (HR, 0.50; 95% CI, 0.06-0.94; 

 = .025). Moreover, the combination regimen demonstrated 1- and 3-year OS rates of 43.6% and 13.9%, respectively, compared with 26.8% and 2.7% with the placebo regimen.

“We believe our NOTABLE trial will be a breakthrough in the field of pancreatic cancer,” co-lead author Shukui Qin, MD, professor and chief physician of the Cancer Center, Jinling Hospital, Nanjing University of Chinese Medicine, said in a press release.

 “The outcomes in this trial may bring new hope to patients with 

Of note, among those who did not need surgery to remove a biliary obstruction, median OS was 11.9 months and 8.5 months with the combination vs the placebo regimens, respectively (HR, 0.54; 95% CI, 0.33-0.88; 

 = .037). Similarly, OS was improved for those who had no surgical history and received treatment with nimotuzumab plus gemcitabine at 15.8 months compared with placebo and gemcitabine at 6.0 months (HR, 0.40; 95% CI, 0.19-0.84).

Median progression-free survival (PFS) was also improved with nimotuzumab plus gemcitabine at 4.2 months vs gemcitabine alone at 3.6 months (HR, 0.56; 95% CI, 0.12-0.99; 

 = .013). For those with no surgical history of biliary obstructions, median PFS was 5.5 months vs 3.4 months in the nimotuzumab and placebo groups, respectively (

The incidence of adverse events (AEs) was similar among both groups. The most common AEs with the anti-epidermal growth factor receptor monoclonal antibody were neutropenia (11.1%), leukopenia (8.9%), and thrombocytopenia (6.7%)

The phase 3 trial evaluated the efficacy and safety of nimotuzumab in combination with gemcitabine versus gemcitabine alone in patients with 

 wild-type locally advanced or metastatic pancreatic cancer. In addition, subgroup analyses were conducted based on the need for surgery to remove bile duct obstructions prior to receiving chemotherapy, as those who do not need surgery to repair obstructions typically have better liver function and no jaundice, indicating a potential advantage for tolerating chemotherapy, according to the release.

In total, 92 patients in China were randomized to receive either 400 mg nimotuzumab every week followed by 1000 mg/m2 gemcitabine on days 1, 8, and 15 of every 28-day cycle or placebo plus gemcitabine until progression or unacceptable toxicity.

OS served as the primary end point, while secondary end points included PFS, objective response rate (ORR), and safety.

“To see any survival benefit in a trial for metastatic pancreatic cancer is of interest,” ASCO expert in gastrointestinal (GI) cancers Cathy Eng, MD, FACP, FASCO, David H. Johnson Chair in Surgical and Medical Oncology, co-leader of the Gastrointestinal Cancer Research Program, professor of medicine (hematology and oncology), co-director of GI oncology, vice-chair of the SWOG GI Committee, and director of the Vanderbilt-Ingram Cancer Center Young Adult Cancers Initiative, said in a press release.

“The investigators have evaluated a subset of pancreatic cancer, 

 wild-type, which is rarely investigated prospectively because this form of the cancer represents less than 10% of all pancreatic cancer patients,” she added. “Additional studies in comparison with the combination of gemcitabine/nab-paclitaxel would be of interest. We should consider validating any potential advances to make a true difference in the lives of all patients with pancreatic cancer.”

1. Qin S, Bai Y, Wang Z, et al. Nimotuzumab combined with gemcitabine versus gemcitabine in KRAS wild‐type locally advanced or metastatic pancreatic cancer: a prospective, randomized‐controlled, double‐blinded, multicenter, and phase III clinical trial. 

. 2022;40(suppl 17):LBA4011. doi:10.1200/JCO.2022.40.17_suppl.LBA4011

2. Nimotuzumab Significantly Improves Overall Survival for K-Ras Wild-Type Advanced Pancreatic Cancer. News release. American Society of Clinical Oncology. June 3, 2022. Accessed June 3, 2022. https://bit.ly/3x4hRve

Patients with KRAS wild-type pancreatic cancer elicited a significant survival benefit with the addition of nimotuzumab to gemcitabine vs placebo plus gemcitabine in a phase 3 trial.

Survival Benefit Observed With Nimotuzumab Plus Chemo in KRAS Wild-Type Advanced Pancreatic Cancer

The addition of ibrutinib (Imbruvica) to rituximab (Rituxan) plus mini-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone [R-mini-CHOP]) to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) resulted in improved progression-free survival (PFS), quality of life (QOL), and function, according to a primary analysis of the Australasian Leukaemia & Lymphoma Group NHL29 Study.

The results were presented during the 2021 ASH Annual Meeting and Exposition.

“The 2-year overall survival [OS] rate in the [standard-of-care group] is 59%, and the 2-year progression-free survival was 47%. We also know that the addition of ibrutinib to full dose R-CHOP in younger patients has efficacy…however, significant toxicity limits the ability to complete therapy in patients 60 years and above,” Emma Verner, MBBS, of the Department of Haematology, Concord Repatriation General Hospital in Australia, said during a presentation of the findings.

“We therefore hypothesized that the addition of ibrutinib to mini-CHOP in elderly patients with diffuse large B-cell lymphoma would be both tolerable and efficacious, improving the 2-year overall survival.”

Following data cutoff of June 6, 2021, median follow-up in 79 patients aged 75 or older was 34.3 months (range, 0.2-66.3). In total, 80% completed 6 cycles of R-mini-CHOP and 71% completed 8 cycles.

The overall response rate was 76%, including 56 complete responses (70%), 5 partial responses (6%), a single patient had stable disease (1%), and 9 with progressive disease (11%). Seven patients (9%) were not evaluable and 2 (2.5%) were missing end of trial response assessments. Response rates did not differ by cell of origin (COO; non-Germinal Centre B [GCB], 82% vs GCB, 71%; 

Although there was a trend toward improved OS, a target of a 15% increase from 59% with the current standard of care was not seen. The 2-year OS with the combination was 68% (95% CI, 57%-78%; 

 = .11). Median OS was not reached (NR; 95% CI, 35-NR); however, this was longer in those with a lower International Prognostic Index (IPI) of 1 to 3 (not reached [NR]) compared with an IPI of 4 (35 months) or 5 (19 months).

Of note, the 2-year PFS with the addition of ibrutinib was 60% (95% CI, 49%-72%; 

 < .03), a significant difference from 47% with the standard of care. Median PFS was 53 months (95% CI, 20-NR).

The COO had no impact on 2-year OS, with the median in GCB (95% CI, 29-NR) and the non-GCB (95% CI, 24-NR) groups not reached (

 = .99). The same was seen with 2-year PFS, with a median in GCB of 30 months (95% CI, 17-NR) and not reached in non-GCB (95% CI, 19-NR; 

Lastly, according to the primary analysis, 2-year disease-free survival (DFS) was 85% (95% CI, 60%-95%), with the median NR (95% CI, 32-NR).

Twenty-eight deaths occurred (35%): 16 due to progressive lymphoma, 5 from infection, 2 from respiratory failure, 2 from other malignancy, 1 from cardiac arrest, 1 from intra-abdominal hemorrhage, and 1 due to gastric hemorrhage.

Almost all patients (99%) experienced at least 1 adverse event (AE), with 24 (30%) reporting with grade 1 to 2, 49 (64%) with grade 3 to 4, and 5 (6%) with grade 5 AEs. The most common grade 3 or greater AEs were lung infection (13%), other infections (11%), anemia (11%), febrile neutropenia (9%), thrombocytopenia (9%), and atrial fibrillation (8%). Serious AEs occurred in 67%, the most common being lung infection (11%), atrial fibrillation (9%), fever (9%), and other infection (9%).

Investigators temporarily stopped treatment with ibrutinib in 62% of patients and permanently stopped treatment in 25%. Treatment discontinuation occurred due to toxicity (11%), progressive disease (6%), patient choice (4%), death (4%), or consent withdrawal (3%).

The study also found that EORTC-QLQ-C30 global health status among patients significantly improved between screening (n = 78; mean [standard deviation], 58 [25]), end of treatment (n = 57; 63 [23]), and 18-month post-treatment (n = 29; 74 [19]) (

 = .007). Patients reported significant reductions in fatigue, nausea and vomiting, pain, insomnia, appetite loss, constipation, and diarrhea. However, the investigators noted that there was no impact of Cumulative Illness Rating Scale-Geriatric score on disease response rate or risk of death.

In the prospective, multicenter, single-arm, phase 2 study, investigators administered six 21-day cycles of ibrutinib at 560 mg plus R-mini-CHOP, comprised of 375mg/m2 rituximab, 400 mg/m2 cyclophosphamide, 25 mg/m2 doxorubicin, 1 mg vincristine on day 1, and prednisone at either 40mg/m2 or 100mg/day for 5 days. Treatment was followed by 2 additional 21-day cycles of rituximab plus ibrutinib.

To be eligible for the trial, patients had to be 75 years or older, have newly diagnosed de novo DLBCL, have an ECOG performance status of 2 or less, and have stage I to IV disease. Patients were excluded if they had central nervous system involvement, required coagulation with warfarin, required dual antiplatelet therapy with aspirin and a P2Y12 antagonist, or a malignancy within 3 years.

Two-year OS served as the primary end point. Secondary end points included response rates, PFS, DFS, and toxicity.

Median age was 81.5 years (range, 75-95). More than half of patients were female (51%), had stage III or IV (81%) disease, and had an IPI risk score of 3 to 5 (63%). On centralized immunohistochemistry (IHC), 57% were non-GCB cell-like subtype and 43% were GCB.

“To conclude, the addition of ibrutinib to mini-CHOP was deliverable, with a respectable 2-year overall survival [rate] of 68%. However, our ambitious target of the 15% increase was not reached in a small sample size,” Verner said. “We are encouraged by our significantly improved progression-free survival of 60%. And despite the considerable, but not unexpected, toxicity in this elderly cohort, the quality of life and functioning improvements in survivors are also promising. This data supports further study of adding Bruton tyrosine kinase inhibitors to mini-CHOP in elderly patients with diffuse large B-cell lymphoma.”

Verner E, Johnston A, Pati N, et al. Efficacy of ibrutinib, rituximab and Mini-CHOP in very elderly patients with newly diagnosed diffuse large B cell lymphoma: primary analysis of the Australasian Leukaemia & Lymphoma Group NHL29 Study. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia. Abstract 304. https://bit.ly/3DIfFuR

Combining ibrutinib with rituximab resulted in improved 2-year progression-free survival among elderly patients with previously untreated diffuse large B-cell lymphoma. 

R-Mini-Chop Plus Ibrutinib Extends Progression-Free Survival in Elderly Patients With Newly Diagnosed DLBCL

Men with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) who are being treated with radium-223 (Xofigo) plus enzalutamide (Xtandi) can reduce their risk of fractures with the use of bone-protecting agents (BPAs), according to findings presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.1

“This safety analysis confirms the importance to give a bone-protecting agent when treating patients with CRPC and bone metastases,” Silke Gillessen, MD, Oncology Institute of Southern Switzerland, said during a presentation of the safety analysis.

In the randomized phase 3 EORTC-1333-GUCG/Peace-3 trial (NCT02194842), investigators randomized patients 1:1 to receive either enzalutamide at 160 mg daily plus radium-223 at 55 kBq/kg every 4 weeks for 6 cycles, or enzalutamide alone.

The study population included patients with bone-predominant mCRPC (≥2 bone metastases); asymptomatic or mildly asymptomatic disease; a WHO performance score of 0 or 1; no prior treatment with cyp17 inhibitors, enzalutamide, other radionucleotides, or hemibody radiotherapy; and no known brain or visceral metastases.

Radiographic progression-free survival served as the primary end point.

Following results of fractures occurring in the ERA223 trial (NCT02043678),2 the investigators of the EORTC-1333-GUCG/PEACE-3 trial decided to send out an urgent safety letter. “In this, it was made mandatory to use a bone-protecting agent in all patients for at least 6 weeks before starting radium-223. In April 2018, an IDMC analysis was done, and the recommendation was to continue the trial, but to use a bone-protecting agent in all patients from both arms,” explained Gillessen. “The IDMC is regularly monitoring the trial, and after the review in December last year, recommended to present the updated numbers regarding bone fractures to the scientific community.”

In her presentation at the 2021 ASCO Annual Meeting, Gillessen offered updated results of the safety analysis from the trial, highlighting the impact of BPAs on fracture rates.

As of the April 2021 cut-off, of the 267 patients randomized to both treatment arms, 74 in each were given BPAs.

Before administering the safety letter, 45.2% of patients had not received a BPA, compared with just 3% who had not after the letter was sent out.

The cumulative incidence of fractures at 1 year was 37.1% (95% CI, 21.3%-53.0%) in the combination arm and 15.6% (95% CI, 5.6%-30.3%) in the enzalutamide alone arm. In men who received a BPA, the 1-year incidence of fractures was reduced to 2.7% (95% CI, 0.5%-8.5%) and 2.6% (95% CI, 0.5%-8.3%), respectively.

At 18 months, the cumulative incidence was 45.9% (95% CI, 28.6%-61.6%) in the combination arm and 21.9% (95% CI, 9.5%-37.5%) in the enzalutamide alone arm, without a BPA. With a BPA, the incidence was 4.3% (95% CI, 1.1%-10.9%) and 2.6% (95% CI, 0.5%-8.3%), respectively.

“According to our study, we will continue and want to motivate all investigators to include [bone-protecting agents in the treatment of] patients. And hopefully, we can still report efficacy results as well. Importantly, the IDMC will also continue to closely monitor the study,” Gillessen said.

Radium-223 is an alpha-emitting radiopharmaceutical that has demonstrated an overall survival benefit in men with mCRPC, with the hypothesis that combining it with a novel androgen receptor (AR) pathway inhibitor could improve clinical outcomes.

In the randomized, double-blind, placebo-controlled ERA223 trial, investigators evaluated the use of concurrent treatment with abiraterone acetate (Zytiga; 1000 mg once daily) plus prednisone (5 mg twice daily) or prednisolone (5 mg twice daily) and radium-223 (55 kBq/kg) in 806 patients with mCRPC.2 Symptomatic skeletal event-free survival served as the primary end point.

BPAs were only permitted in the trial if a patient was receiving them at baseline. Initiation of such agents during the study was prohibited to prevent confounding effects. Therefore, only 60% of patients had not received a BPA at study entry.

In a posthoc analysis of the trial, BPAs significantly reduced the rate of fractures in both treatment arms.

“To better understand the nature of these fractures, an independent review of the fracture events was performed. Interestingly, the maturity of fractures in both groups occurred at sites with no detectable metastasis and were considered osteoporotic or traumatic,” Gillessen explained.

“Treatment with [androgen-deprivation therapy (ADT)] can induce bone loss. And we know that bone-protecting agents can be used in this bone loss and also in osteoporotic fractures in men treated with ADT,” Gillessen said. “Bone protecting agents can also delay the time to a first skeletal-related event [SRE] in men with castration-resistant prostate cancer and bone metastasis.”

Skeletal complications may be common in patients with advanced prostate cancer and result in 2 distinct mechanisms, she added: frailty, or osteoporotic fractures are reported in 11% of patients and SREs occur in up to 40% of those treated with ADT and an AR pathway inhibitor.

“To prevent these SREs, many guidelines recommend using bone-protecting agents for patients with castration-resistant prostate cancer and bone metastasis. Combining gamma radiation and hormonal manipulation is a well validated treatment strategy in prostate cancer,” Gillessen said.

1. Gillessen S, Choudhury A, Rodriguez-Vida A, et al. Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis. 

. 2021;39:(suppl 15; abstr 5002). doi: 10.1200/JCO.2021.39.15_suppl.5002.

2. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. 

Men with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer who are being treated with radium-223 (Xofigo) plus enzalutamide (Xtandi) can reduce their risk of fractures with the use of bone-protecting agents.

Bone-Protecting Agents Reduce Fracture Risk During Prostate Cancer Treatment

Treatment with the second-generation 4-1BB bi-specific chimeric antigen receptor (CAR) T-cell therapy C-CAR039 led to improved response rates – as well as a favorable safety profile – in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL), according to phase 1 data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

“C-CAR039 has demonstrated a favorable safety profile and highly promising efficacy in patients with relapsed/refractory B-NHL,” Aibin Liang, MD, Tongji Hospital of Tongji University, Shanghai, China, said during an oral presentation of the data.

According to the safety data, 100% of patients experienced at least 1 adverse event (AE) of any grade.

In total, 92.9% of patients reported cytokine release syndrome (CRS); however, Liang noted, that most were grade 1 or 2 and all events were reversible. Only 1 patient, who was treated in the 2.5x106 CAR T cells/kg, experienced grade 3 CRS. The most common symptoms were pyrexia (100%) and hypotension (23.1%).

The median time to onset of CRS events was 2.5 days (range, 0-10), with a median time to resolution of 4 days (range, 1-25). CRS cases were treated with tocilizumab (14.3%), corticosteroids (3.6%), or a combination of the 2 (3.6%).

Two cases of neurologic events – both in the 5.0x106 CAR T cells/kg group – occurred at a median time of onset of 16 days (range, 4-28). The median time to resolution was 31.5 days (range, 11-52).

“CRS in higher dose groups showed shorter time to onset and longer resolution time,” Liang said.

Cytopenias were common, “mostly related to Cy/Flu lymphodepletion and are reversible,” he added, noting that infection was also common, occurring in 53.6% of patients, with only 1 grade 3 event.

The most common grade 3 or higher AEs included lymphopenia (96.$%), leukopenia (89.3%), neutropenia (89.3%), anemia (32.1%), and thrombocytopenia (25%).

For efficacy, median follow-up was 7 months (range, 1.9-17.2).

The overall response rate (ORR) was 92.6% for the entire population, including an 85.2% complete response (CR) rate, 7.4% partial response (PR) rate, 3.7% with stable disease (SD), and 3.7% with progressive disease (PD). Broken down by disease subtype, ORR in those with diffuse large B-Cell Lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), follicular lymphoma (FL), and tFL were 91.7% (CR, 83.3%; PR, 8.3%), 100% (CR, 100%), 100% (CR, 100%), and 100% (CR, 100%), respectively. Liang noted that the CR rate was consistent among key subgroups, including dose level, disease type, cell or origin of cancer, age, sex, stage, IPI, double expressors, extranodal disease, prior lines of therapy, previous response status, previous ASCT, and bridging treatment.

The median time to first response was 1 month (range, 0.9-1.6), as was median time to CR (range, 0.9-6.0). Four patients relapsed at 3, 6, 8, and 9 months, respectively, after achieving CR. Median duration of response (DOR) has not been reached. The 6-month progression-free survival (PFS) was 83.2% (95% CI, 69.1-100).

“C-CAR039 proliferation and expansion in the peripheral blood correlated with B cell depletion,” Liang added.

C-CAR039 – a novel second generation 4-1BB bi-specific CAR T-cell therapy that targets both CD19 and cd20 antigens – has demonstrated in vitro anti-tumor activity against both single- and double-positive CD20/CD19-expressing tumors, as well as superior anti-tumor activity in both in vitro and in vivo to the bi-specific CAR T-cell therapy with the tandem linked scFvs of Leu16 and FMC63, Liang explained.

“This data strongly support moving this CAR design to clinic use as the lead asset,” he added.

Manufacturing the CAR T-cell therapy was carried out in a functionally closed, highly automated serum free system within a median of 6 days (range, 5-11). Median vein-to-vein time was 19 days (range, 12-67).

Dose escalation and expansion studies were conducted to evaluate the safety and efficacy of C-CAR039 in r/r B-NHL patients. C-CAR039 was administered as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen.

The phase 1 study is an open-label, dose escalation and expansion study conducted across 4 sites in China – designed to evaluate the safety and efficacy of this approach in patients with relapsed/refractory B-NHL.

Investigators administered C-CAR039 as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen.

Eligibility criteria included patients aged 18 to 75 years; relapsed/refractory B-NHL, including DLBCL, FL, and mantle cell lymphoma (MCL); either CD19- or CD20-positive disease; no active central nervous system (CNS) involvement; and have received anti-CD20 monoclonal antibodies.

The safety assessment included the incidence and severity of treatment-emergent adverse events (TRAEs), while the efficacy assessment was comprised of ORR, DOR, PFS, and OS.

In the trial, patients were treated across 3 doses: 1.0x106 CAR T cells/kg (DL1), 2.5x106 CAR T cells/kg (DL2), and 5.0x106 CAR T cells/kg (DL3).

As of April 20, 2021, 34 patients were infused with C-CAR039. In total, 28 were evaluable for safety, including 4 in the DL1 arm, 15 in the DL2 arm, and 9 in the DL3 arm; while 27 were evaluable for efficacy, including 4 in the DL1 arm, 15 in the DL2 arm, and 8 in the DL3 arm.

Median age was 55.5 years (range, 28-71). The majority of patients were male (89.3%), had diffuse large B-cell lymphoma (89.3%), an ECOG performance score of 0 (64.3%), and were Ann Arbor stage III/IV (75%). Moreover, 8 patients (28.6%) had double-expressor lymphoma.

The median number of prior lines of therapy was 3 (range, 1-5), including ASCT (17.9%), a BTK inhibitor (28.6%), and lenalidomide (Revlimid; 32.1%). Eight patients (28.6%) had never experienced a CR to prior therapies and 5 patients (17.9%) received bridging therapy.

“The early clinical efficacy signal is encouraging and compares favorably to anti-CD19 CAR T and peer therapies,” the study authors concluded. “These findings will be evaluated in more patients with longer follow-up to confirm safety, efficacy and duration of response.”

Liang A, Zhou L, Li P, et al. Safety and efficacy of a novel anti-CD20/CD19 bi-specific CAR T-cell therapy (C-CAR039) in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). 

. 2021;39:suppl 15; abstr 2507. doi: 10.1200/JCO.2021.39.15_suppl.2507.

The second-generation 4-1BB bi-specific CAR T-cell therapy was efficacious and safe in treating patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Second-Generation CAR T-Cell Therapy Is ‘Highly Promising’ in Relapsed/Refractory B-NHL

The FDA approved nivolumab (Opdivo) for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy, according to Bristol Meyers Squibb — the agent’s manufacturer.

The agency based the priority review and approval on results from the multicenter, randomized, active-controlled, open-label global phase 3 ATTRACTION-3 trial — designed to evaluate nivolumab (n = 210), compared with taxane chemotherapy (docetaxel or paclitaxel; n = 209). The trial included patients regardless of tumor PD-L1 status.

Researchers randomized patients to receive either 240 mg IV nivolumab over 30 minutes every 2 weeks or investigator’s choice of taxane chemotherapy (either 75 mg/m2 IV docetaxel every 3 weeks [n = 65] or 100 mg/m2 paclitaxel once a week for 6 weeks followed by 1 week off [n = 144]). Patients were treated until disease progression or unacceptable toxicity.

Overall survival (OS) served as the primary end point. Secondary end points included investigator-assessed overall response rate (ORR) and progression-free survival (PFS), and duration of response (DOR).

In the trial, patients treated with Opdivo demonstrated superior median OS, compared with chemotherapy (10.9 months versus 8.4 months).

Researchers found no statistically significant difference in ORR (19.3% [95% CI, 13.7-26.0] vs 21.5% [95% CI, 15.4-28.8]; 

 = .6323) between the 2 arms. Among patients treated with nivolumab, 0.6% experienced a complete response and 18.7% with a partial response, compared with those treated with chemotherapy (1.3% and 20.3%, respectively).

Median PFD was 1.7 months (95% CI, 1.5-2.7) in the Opdivo arm, compared with 3.4 months (95% CI. 3.0-4.2) in the investigator’s choice chemotherapy arm (HR, 1.1; 95% CI, 0.9-1.3).

Safety was evaluated in 209 patients. Serious adverse events (AEs) occurred in 38% of patients given nivolumab, including pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. Fatal AEs consisted of interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).

Treatment was discontinued in 3% of patients and was delayed in 27% of patients due to AEs.

The most common AEs, occurring in 20% or more of patients treated with nivolumab, included rash (22%) and decreased appetite (21%).

“Many cases of esophageal cancer are diagnosed at the advanced stage, when the disease could have a significant impact on a patient’s health. Treatment options can be limited once patients with advanced esophageal squamous cell carcinoma progress,” Adam Lenkowsky, general manager and head of US oncology, immunology and cardiovascular at Bristol Myers Squibb, said in a press release.

“The approval of Opdivo as a new treatment option for previously treated patients with advanced esophageal squamous cell carcinoma, regardless of PD-L1 expression, highlights our commitment to providing new options to address the unmet needs of patients and brings us another step closer to understanding the full potential of immunotherapy for gastrointestinal cancers,” he added.

Bristol Meyers Squibb. U.S. Food and Drug Administration Approves Opdivo® (nivolumab) for the Treatment of Patients with Advanced Esophageal Squamous Cell Carcinoma (ESCC) After Prior Fluoropyrimidine- and Platinum-based Chemotherapy. Published June 10, 2020. 

https://news.bms.com/press-release/corporatefinancial-news/us-food-and-drug-administration-approves-opdivo-nivolumab-trea

FDA Approves Nivolumab to Treat Advanced Esophageal Squamous Cell Carcinoma

 sat down with Brian Rini, MD, from the Vanderbilt-Ingram Cancer Center (VICC), to discuss results from the phase III TIVO03 trial, and its potential impact on patients with relapsed or refractory renal cell carcinoma.

As you know, there are several VEGF TKIs that are approved. So, the biggest advantage to tivozanib (Fotivda) is tolerability. It’s a very clean drug, hits VEGF pretty much, and has a very good tolerability profile in terms of side effects and need for dose interruption or reduction — which is very minimal. One thing where my mindset has changed now that we have immune therapy combinations that can be curative, is that when we are using single agent TKIs, we’re really just trying to control disease. Because we’re not curing those patients, and they can be on (TKI therapy) for many months or years, tolerability is really the key thing. I don’t think there are huge efficacy differences among TKIs. There are some – tivozanib was better than sorafenib in the TIVO-3 trial – but at the end of the day, in my opinion, it’s really more about tolerability.

Patients, appropriately, always want more options. I’ve never met a patient who doesn’t look down the road a little bit and say, “Gee doc, if this one doesn’t work, is there something else?” I totally get it. So, I think even though we on the physician side might say, “Do we really need another TKI?” From a patient standpoint, they absolutely want more options. Having a tolerable options, especially in this late line setting, is a potential advantage to patients. I often describe to patients that we’re just trying to get as many shots on goal as possible. You never know when one drug might work wonderfully or not at all. Even among the VEGF TKIs, they work differently in different patients for reasons I don’t think we understand. So, I think it adds to our weapons in this disease.

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Oncology Nursing News sat down with Brian Rini, MD, from the Vanderbilt-Ingram Cancer Center (VICC), to discuss results from the phase III TIVO03 trial, and its potential impact on patients with relapsed or refractory renal cell carcinoma.

Tivozanib Tolerability Shows Potential Advantage for Patients with Advanced RCC

Integration of a comprehensive geriatric assessment with geriatrician-led management care improved health-related quality of life (HRQOL), unplanned hospital admissions, and treatment discontinuation among older adults undergoing systemic therapy for their cancer, according to results from the INTEGERATE study presented during a 2020 ASCO Virtual Scientific Program press briefing.

Of note, this is the first randomized study involving both geriatricians and oncologists for the care of older adults with cancer, according to the researchers.

“We found that oncogeriatric care in older people with cancer about to receive anti-cancer therapy led to significant improvements in health outcomes — at the patient level, quality of life, as well as the system level’s outcomes, such as hospital utilization and treatment delivery,” lead author Wee-Kheng Soo, MBBS, FRACP, a geriatrician and medical oncologist at Eastern Health in Melbourne, Australia, said during a pre-recorded presentation. “These findings suggest that those aged 70 or older with cancer should receive a geriatric clinical assessment to optimize their care and health outcomes.”

In the prospective, randomized, parallel-group, open-label study, those who received the intervention — which is a detailed systematic evaluation identifying medical, psychosocial, and functional limitations – had improved Elderly Functional Index (ELFI) scores, compared with those who received usual care across all follow-up points. However, the maximal difference in scores was seen at week 18 (estimated marginal mean ELFI score, 72.0 vs 58.7; 95% CI, 5.5-21.2; P = 0.001), but this was reduced by week 24 (estimated marginal mean ELFI score, 73.1 vs 64.6; 95% CI, 0.5-16.5; P = 0.037).

The intervention group also experienced improvements in functioning, mobility, burden of illness, and future worries, which persisted to the end of the study.

Moreover, the researchers saw an average of 1.3 fewer emergency room visits (39%) and 1.2 fewer unplanned hospital admissions per person per year (43%; P < .001), as well as a reduction in early treatment discontinuations (32.9% vs 53.2%; P = 0.01) among those who received intervention versus those who did not. Soo attributed the decline to be driven by reduced treatment-related toxicity and pointed out this could potentially be cost saving. Lastly, the number of overnight stays geriatric patients with cancer had decreased by 7 days per person per year (24%).

The trial included 154 patients aged >70 years with cancer planned for chemotherapy, targeted therapy, or immunotherapy. Patients were randomized 1:1 to receive either geriatrician-led comprehensive geriatric assessment and management integrated with usual care (n = 76) or usual care alone (n = 78).

HRQOL — the primary end point – consisted of physical, role and social functioning; mobility, burden of illness and future worries, and was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-ELD14 at 0, 12, 18, and 24 weeks. Secondary end points included function, mood, nutrition, health utility, treatment delivery, healthcare utilization, and survival.

The assessment was conducted through self-reported questionnaires and a comprehensive assessment by a geriatrician.

Thirteen patients died by week 12 and 130 (92.2% of the remaining patients) completed at least two primary outcome assessments.

“Currently, a person with cancer is typically referred to a geriatrician only in the later stages of their illness when they experience significant problems with completing everyday tasks,” the ASCO-issued release stated. “However, an integrated approach involving comprehensive geriatric assessment and early geriatrician involvement (also known as ‘integrated oncogeriatric care’) can help create a coordinated plan to optimize the older person with cancer.”

The researchers intend to implement the integrated comprehensive geriatric assessment in a large, multicenter implementation study comparing different care models in geriatric oncology and different cancer settings.

“The number of people worldwide over the age of 65 is expected to continue to grow, making the need for more rigorous research to help optimize the quality of care we provide to older patients an urgent priority. This study shows that geriatric assessments lead to clear improvements in quality of life and better care planning for older patients with cancer,” Howard A. Burris III, MD, FACP, FASCO, ASCO president, said in the release.

Soo WK. Integrated geriatric assessment and treatment (INTEGERATE) in older people with cancer planned for systemic anticancer therapy. Presented at: 2020 ASCO Virtual Scientific Program; May 12, 2020. Abstract 1201

ASCO press release. Integrating Geriatric Assessment and Management Into Cancer Care Improves Quality of Life, Reduces Hospital Admissions for Older Patients. Available from: https://www.asco.org/about-asco/press-center/news-releases/integrating-geriatric-assessment-and-management-cancer-care. Published May 13, 2020. Accessed May 13, 2020.

This article originally appeared on OncLive, titled “

Integrated Geriatric Assessment Optimizes Care for Older Adults with Cancer.

By integrating a comprehensive geriatric assessment with geriatrician-led management care researchers found an improved quality of life for older adults with cancer.
 

Integrated Geriatric Assessment Optimizes Care for Older Adults with Cancer

The FDA approved the combination use of encorafenib (Braftovi) and cetuximab (Erbitux) for the treatment of adult patients with 

-positive metastatic colorectal cancer (mCRC), as detected by an FDA-approved test, after prior therapy, according to Pfizer.

 mutations are estimated to occur in up to 15% of people with metastatic colorectal cancer and represent a poor prognosis for these patients,” lead study investigator Scott Kopetz, MD, PhD, FACP, associate professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, said in a press release. “As the first-and-only targeted regimen for people with BRAF

-mutant metastatic CRC who have received prior therapy, Braftovi in combination with cetuximab is a much-needed new treatment option for these patients.”

The approval is based on findings from the international open-label phase III BEACON CRC study, which were published in 2019 in the New England Journal of Medicine.

 The trial evaluated encorafenib plus cetuximab with or without binimetinib (Mektovi) in 665 patients with 

-positive mCRC whose disease had progressed after 1 or 2 prior regimens.

Patients were randomly assigned in a 1:1:1 ratio to the targeted therapy triplet of encorafenib, binimetinib, and cetuximab; the targeted therapy doublet of encorafenib and cetuximab; or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan).

Results showed that the doublet demonstrated an improvement in overall survival (8.4 months [95% CI, 7.5-11.0] vs 5.4 months [95% CI, 4.8-6.6]; HR, 0.60; 95% CI, 0.45-0.79); 

 = .0003) objective response rates (20.0% [95% CI, 13.0%-29.0%] vs 2.0% [95% CI, 0.0%-7.0%]; 

 < .0001), and median progression-free survival (4.2 months [95% CI, 3.7-5.4] vs 1.5 months [95% CI, 1.4-1.7]; HR, 0.40; 95% CI, 0.31-0.52; 

 < .0001), compared with cetuximab plus irinotecan-containing regimens.

The most common adverse events (AEs; ≥ 25%) seen in patients treated with encorafenib in combination with cetuximab were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia and rash.

“We are pleased by the FDA’s approval of Braftovi in combination with cetuximab, as we are committed to developing targeted medicines that can help people living with certain mutation-driven cancers,” Chris Boshoff, MD, PhD, chief development officer of oncology at Pfizer Global Product Development, said in the release. “We are grateful to the patients and study investigators who participated in the phase III BEACON CRC trial and are proud to now be able to offer a targeted treatment option for people with BRAF

-mutant metastatic CRC who have received prior therapy. Looking ahead, we’re committed to continuing to investigate this treatment regimen across earlier lines of therapy.”

The FDA previously granted the triplet regimen a breakthrough therapy designation for the treatment of patients with BRAF

-mutant mCRC as detected by an FDA-approved test, following failure of 1 or 2 prior lines of treatment. Additionally, the triplet regimen has been included as a category 2A treatment for patients with BRAF

-mutant mCRC, following failure of 1 or 2 prior lines of therapy in National Comprehensive Cancer Network guidelines for colon and rectal cancers in the United States.

The ongoing phase II ANCHOR-CRC study (NCT03693170) is investigating the triplet as frontline treatment for patients with BRAF

1. U.S. FDA APPROVES BRAFTOVI® (ENCORAFENIB) IN COMBINATION WITH CETUXIMAB FOR THE TREATMENT OF BRAFV600E-MUTANT METASTATIC COLORECTAL CANCER (CRC) AFTER PRIOR THERAPY. Published April 8, 2020. https://www.pfizer.com/news/press-release/press-release-detail/u_s_fda_approves_braftovi_encorafenib_in_combination_with_cetuximab_for_the_treatment_of_brafv600e_mutant_metastatic_colorectal_cancer_crc_after_prior_therapy. Accessed April 8, 2020.

2. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. 

The FDA approved the combination use of encorafenib and cetuximab for the treatment of adult patients with BRAFV600E-positive metastatic colorectal cancer.
 

FDA Approves Encorafenib Plus Cetuximab for Metastatic CRC with BRAF V600E Mutation

The FDA granted full approval to pemetrexed (Pemfexy), a liquid injection and branded alternative to Alimta, for the treatment of patients with nonsquamous non-small cell lung cancer (NSCLC), according to Eagle Pharmaceuticals.

The agency granted full approval to pemetrexed for injection (Pemfexy), a liquid injection and branded alternative to Alimta, for nonsquamous NSCLC.
 

Kristie L. Kahl