Conor Killmurray

Drug manufacturer GSK pulls its monotherapy treatment for previously treated adult patients with relapsed or refractory multiple myeloma (RRMM) belantamab mafodotin-blmf (Blenrep) following a request from the FDA, according to a press release from GSK.

The FDA request to withdraw belantamab’s US marketing authorization is based on the previous results of the open label, randomized phase 3 confirmatory DREAMM-3 trial (NCT04162210) that did not meet the requirements of the FDA’s accelerated approval program. The trial compared belantamab monotherapy to pomalidomide in combination with low dose dexamethasone (PomDex) in RRMM patients who were treated with at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

“We respect the Agency’s approach to the accelerated approval regulations and associated process. Multiple myeloma is a challenging disease, with poor outcomes for patients whose disease has become resistant to standard-of-care treatments,” said Sabine Luik, Chief Medical Officer of GSK, in the press release. “We will continue the DREAMM clinical trial program and work with the US FDA on a path forward for this important treatment option for patients with multiple myeloma.”

In the update of the DREAMM-3 trial the primary endpoint of median progression-free survival (PFS) between the two cohorts was longer in the monotherapy group at 11.2 months compared with 7 months in the combination cohort (HR 1.03; 95% CI, 0.72-1.47).

 The ORR was also higher in the belantamab group at 41% vs 36% for patients on PomDex, and belantamab showed a deeper response than PomDex with a 25% very good partial response (VGPR) in the monotherapy group vs 8% in the combination arm.

Other secondary endpoints included duration of response (DOR) and overall survival (OS), but the median DOR was not reached in the belantamab group compared with 8.5 months in the PomDex group, but at 12 months the DOR rates favored patients on belantamab at 76.8% vs 48.4% in the PomDex arm. OS had only achieved a 37.5% overall maturity with median OS being virtually identical between the 2 arms at a median OS of 21.2 months in the belantamab arm and 21.1 months in the PomDex arm (HR 1.14; 95% CI, 0.77, 1.68).

The FDA had originally granted an accelerated approval to belantamab based off the results of the phase 2 DREAMM-2 study that looked at patients either on 2.5-mg/kg or 3.4-mg/kg of belantamab monotherapy.

 However, this approval was contingent on a confirmed clinical benefit in a phase 3 trial and the update of the DREAMM-3 trial did not show to the FDA enough of a benefit nor statistically significant result.

The original results of the DREAMM-2 study were presented at the 2020 ASCO meeting showed that at 13 month follow up among 31 of the 97 patients on 2.5-mg/kg of belantamab there was an overall response rate (ORR) of 32% (97.5% CI, 21.7-43.6) compared with a 35% ORR in 35 of the 99 patients on 3.4-mg/kg of belantamab (97.5% CI, 23.9-46.0).

 In both the 2.5-mg/kg group and 3.4-mg/kg group VGPR was observed at 58% compared with 66%, respectively.

Safety and tolerability in the phase 3 trial was consistent with previous safety and tolerability results show with belantamab and no new safety signals were observed in this study. In the phase 2 trial adverse events (AEs) of any grade occurred in most patients in both cohorts with treatment-related AEs happening in 88% of patients in the 2.5-mg/kg cohort vs 95% in the 3.5-mg.kg cohort. The most common grade 3 or higher AEs in all patients were keratopathy in 46% of the 2.5-mg/kg cohort and 42% in the 3.4-mg/kg cohort, anemia in 21% and 27%, thrombocytopenia in 22% and 32%, lymphocyte count decreased in 13% and 7%, and neutropenia in 11% and 7%, respectively.

“GSK continues to believe, based on the totality of data available from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development program, that the benefit-risk profile of belantamab mafodotin remains favorable in this hard-to-treat RRMM patient population,” wrote the company in their press release.

GSK stated that patients currently on belantamab and enrolled in the 

 Risk Evaluation and Mitigation Strategy program will have the option to enroll in a further compassionate use program to continue using the monotherapy. Moreover, they are notifying patients currently on belantamab that they should consult their healthcare provider.

Trials are still ongoing with the monotherapy including the DREAMM-7 and DREAMM-8 studies that are looking to evaluate the efficacy of belantamab in combination with bortezomib and dexamethasone vs daratumumab in combination with bortezomib and dexamethasone and belantamab in combination with pomalidomide and dexamethasone compared with that of a combination of pomalidomide, bortezomib and dexamethasone, respectively.  

1. GSK provides an update on Blenrep (belantamab mafodotin-blmf) US marketing authorization. News Release. GlaxoSmithKline plc. November 22, 2022. Accessed: November 22, 2022. https://bit.ly/3EwodY1 

2. GSK provides update on DREAMM-3 phase III trial for Blenrep in relapsed/refractory multiple myeloma. News release. GlaxoSmithKline plc. November 7th, 2022. Accessed: November 22, 2022. https://bit.ly/3gwmjib 

3. FDA approves GSK’s BLENREP (belantamab mafodotin-blmf) for the treatment of patients with relapsed or refractory multiple myeloma. News release. GlaxoSmithKline plc. August 5, 2020. Accessed: November 22, 2022. https://bit.ly/31uAclA

4. Lonial S, Lee HC, Badros A, et al. Pivotal DREAMM-2 study: single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) refractory to proteasome inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mAbs). Data presented as part of 2020 American Society of Clinical Oncology Virtual Scientific Program; May 29-31, 2020. Abstract 8536.

Articles

After an update from the phase 3 DREAMM-3 study the use of belantamab monotherapy for previously treated patients with relapsed or refractory multiple myeloma was pulled from US market authorization by request of the FDA.

FDA Requests Belantamab Mafodotin for R/R Multiple Myeloma Be Pulled From US Market

Event-free survival at 24 months (EFS24) has been accepted as an important end point in clinical studies of patients with certain hematologic malignancies and has begun to show its potential effectiveness as a prognostic factor for patients with mantle cell lymphoma (MCL), according to results of an analysis from the Mayo Clinic.

Researchers looked at patients enrolled in the molecular epidemiology resource (MER), a prospective cohort study, diagnosed with MCL from September 2002 through June 2015. They then split the patients into 2 groups to observe, from patients diagnosed through 2002-2009 defined as Era 1 (n = 175) and 2010-2015 defined as Era 2 (n = 168). The split came from identifying time periods in which there was an evolving frontline therapy pattern associated with improved EFS and overall survival (OS).

What the researchers found was patients diagnosed in Era 2 had a better OS with a 5-year OS of 68.4% compared with 59.2% in Era 1 (HR 0.68; 95% CI, 0.50-0.93). Moreover, EFS was favored in the Era 1 group as a sign that EFS impacted OS, but according to the researchers further research is needed to confirm the prognostic role of EFS24.

In order to compare EFS24 of patients with MCL, the researchers compared OS in this group to the expected survival of the general US population. At the time of diagnosis in era 1 (n =176) the Standardized mortality ratio (SMR) between the general US population and survival of patients with MCL was 3.26 (95% CI, 2.7-3.89, 

 < 2.22e-16). In comparison the SMR between the general population and patients with MCL in Era 2 (n = 168) was 2.63 (95% CI, 2.03-3.36, 

Then assessing patients in both eras who had EFS for 24 months the SMR went down, for instance, in era 1 after EFS24 (n = 98) the SMR was 2.23 (95% CI, 1.67-2.92, 

 = 3.86e-09) between patients with MCL and the general population. Moreover, in era 2 after EFS24 (n = 99) the SMR between patients with MCL and the US population was 1.31 (95% CI, 0.78-2.07, 

Patients the researchers looked at included mostly patients with a median age of 64-years-old and given an intermediate score of 4-5 on the simplified mantle cell lymphoma international prognostic indicator at 55 patients in era 1 and 52 patients in era 2. Most patients were also treated with R-CHOP or an R-CHOP like regimen at 92 patients in era 1, but slightly more patients in era 2 were treated with R-bendamustine with 49 patients compared to 43 patients in R-CHOP in era 2.

The researchers attributed the better survival results in Era 2 as MCL survival has likely improved because of frontline therapies and better salvage treatments, such as lenalidomide (Revlimid) and burton’s tyrosine kinase inhibitors. They also noted that patients after EFS24 had a low risk of dying from lymphoma.

The cause of death in era 1 and era 2 at 2 years and 5 years was still highest in the lymphoma death category at 14.9% (95% CI, 10.4%-21.3%) vs 28.2% (95% CI, 22.2%-35.7%) and 14.3% (95% CI, 9.9%-20.8%) vs 20.5% (95% CI, 15.2%-27.7%), respectively. After EFS24 lymphoma death remained the highest cause of death in era 1 at 5 years with 19.8% (95% CI, 13.2%-29.8%) of patients but at 2 years was at 6.1% (95% CI, 2.8%-13.3%) compared with 4.1% (95% CI, 1.6%-10.7%) of patients whose cause of death was non-lymphoma related.

In Era 2 after EFS24 lymphoma death went drastically down at 1% of patients at 2 years and 2.1% of patients in 5 years. Non-lymphoma death was higher both at 2 years and 5 years in era 2 after EFS24 at 4% (95% CI, 1.5%-10.6%) and 5.5% (95% CI, 2.3%-13.1%) at 5 years than lymphoma death in both these time frames.

Notably, for patients in era 2 treated with immunochemotherapy the cause of death due to lymphoma was only present at 5 years in 1.3% (95% CI, 0.2-8.9%) of patients compared with 4.9% (95% CI, 1.9%-12.8%) of all non-lymphoma death. SMR of patients in era 2 treated with immunochemotherapy was also 0.89 (95% CI, 0.43-1.64, 

 = 0.82) after EFS24, whereas SMR after EFS24 in era 1 was 2.89 (95% CI, 2-4.04, 

Wang Y, Larson M, Castellino A, et al. Prognostic Role of Event-free Survival at 24 months (EFS24) in Newly Diagnosed Mantle Cell Lymphoma. Poster presented at the 2022 Annual Society of Hematology Oncology conference. September 28th-October 1st, 2022. Accessed: November 18, 2022.

An analysis of data from 2002-2015 shows that for patients with mantle cell lymphoma achieving event-free survival after two years may be a prognostic factor for better overall survival outcomes.

Achieving EFS After 2 Years Shows Signs of Promising OS in MCL  

Use of the novel agent CUE-101 as monotherapy and in combination with pembrolizumab (Keytruda) showed promising safety and efficacy signs in patients with recurrent/metastatic human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC), according to a press release.

An open-label, 4-part, phase 1b trial (NCT03978689) showed an overall response rate (ORR) of 40% and a 70% clinical benefit rate (CBR) in the first 10 patients given the recommended phase 2 dose (RP2D) of 4 mg/kg of CUE-101 and 200 mg of pembrolizumab given every 3 weeks. Among these responses, there were 4 confirmed partial responses (cPR) and 3 durable stable disease (DSD) at 12 weeks or longer. In an expansion of the phase 1b trial, monotherapy of CUE-101 continued to show these promising responses, but data was not yet matured.

Findings were reported in a poster presentation at the Society for Immunotherapy of Cancer’s 37th Annual Meeting. These results showed that tumor reduction from baseline in 5 patients with cPRs was between 35%-69%.

“We are very encouraged with the overall response rate observed in the trial so far with CUE-101, and its potential to improve standard of care for [patients with] HPV-positive head and neck cancer,” said Christine Chung, MD, chair, department of Head and Neck-Endocrine Oncology at the Moffitt Cancer Center, and a principal investigator in the trial, in the press release. “There is an urgent need for more effective and durable treatment options with less side effects as more than half of all patients with recurrent/metastatic HNSCC given the current standard of care will experience disease progression. I look forward to following this promising CUE-101 clinical data through.”

Within the monotherapy expansion arm, there was a 42% overall CBR, 1 PR of longer than 42 weeks, and 7 patients with DSD. The median overall survival (OS) was trending greater than 12 months for patients in the 3rd line and beyond setting. However, these data are not mature at this time. Twelve patients were still alive of the cohort looking at OS who were given the RP2D. The best change in their disease was also seen in the 4 mg/kg of pembrolizumab and the CUE-101 cohort with treatment ongoing in 7 patients.

“This new data from our combination study demonstrates early evidence of complementary mechanistic activity of CUE-101 with pembrolizumab. In addition, the sustained clinical benefit rate with CUE-101 as monotherapy is very encouraging and has continued to demonstrate proof-of-concept of CUE-101 as a single agent,” said Ken Pienta, MD, acting chief medical officer of Cue Biopharma, in the press release. “Overall, the data shows the potential of CUE-101 to provide patients with an improved clinical benefit rate and with lower toxicity than current standard of care. We look forward to continuing to evaluate data from the trial in addition to defining the potential registrational trial for CUE-101, which we anticipate in mid-2023.”

In the overall study, 49 patients were given CUE-101 as a monotherapy with the 4 mg/kg cohort being expanded to 20 patients, but 17 patients were ultimately treated. Patients had a median age of 62.4 years, 10 patients had an ECOG performance status of 0, and 7 patients had a score of 1.

Nine patients had a CPS score of 1-20 and 8 patients had a CPS score of 20 or more. Twelve patients had a platinum-based therapy prior to treatment, 1 patient was on a checkpoint inhibitor, 1 patient was on PD-L1 inhibitor, 2 patients were on an EGFR inhibitor, and 4 patients had no prior treatment.

Safety data did not show any new safety signals and the continued accrual of these data showed that adverse events (AEs) were consistent with CUE-101 mechanisms of action and underlying disease. Overall, 95.5% of patients had an adverse event (AE) of any grade compared with 40.9% who experienced grade 3 or higher AEs. However, 81.8% of patients treated in this study thus far had a treatment related AE of any grade with 24.1% being grade 3 or higher. The most common treatment-related AEs of any grade were fatigue (30.3%), chills (22.7%), infusion related reaction (25.8%), and nausea (18.2%), with the most common grade 3 or higher AE being fatigue (3%).

“Initiation of the phase 1 trial evaluating our second IL-2-based biologic, CUE-102, is also an important milestone for the company as we continue to demonstrate the versatility and modularity of our platform to potentially treat multiple cancers,” concluded Anish Suri, PhD, president, and chief scientific officer of Cue Biopharma, in the press release.

1. Cue biopharma presents new positive data from ongoing phase 1 trial of CUE-101 in combination with KEYTRUDA(R) for recurrent/metastatic HPV+ head and neck cancer at the society for immunotherapy of cancer’s (SITC) 37th annual meeting. Cue Biopharm, Inc. November 10, 2022. Accessed November 14, 2022. https://yhoo.it/3hvP6Dx

2. Chung C, Colevas A, Adkins d, et al. A phase 1 study of CUE-101, a novel HPV16 E7-pHLA-IL2-Fc fusion protein, as monotherapy and in combination with pembrolizumab in patients with recurrent/metastatic HPV16+ head and neck cancer. Presented at: Society for Immunotherapy of Cancer’s 37th Annual Meeting; November 10th-14th, 2022; Boston, MA. Abstract 607. Accessed November 14, 2022. https://bit.ly/3UUUM8z

Treatment with CUE-101 continued to show promise for patients with head and neck squamous cell carcinoma when combined with pembrolizumab or used as a monotherapy.  

Novel Agent CUE-101 Shows Promise in Recurrent/Metastatic HNSCC

The continuation of enzalutamide (Xtandi) maintenance therapy for patients with metastatic castration resistant prostate cancer (mCRPC) on docetaxel plus androgen deprivation therapy delayed the time to progression of disease when compared with placebo, according to results published in 

Findings from the 2-period, multinational, double-blind, randomized, placebo-controlled, phase 3b PRESIDE study (NCT02288247) showed that in the 136 patients given 160 mg of enzalutamide plus 75 mg/m

 of docetaxel and 10 mg of prednisone they had a significant improvement to the risk of their progression compared with 135 on placebo and the same amount of docetaxel and prednisone.

The median progression-free survival (PFS) was 9.5 months (95% CI, 8.3-10.9) in the enzalutamide group in comparison to 8.3 months (95% CI, 6.3-8.7) in the placebo group (HR 0.72; 95% CI 0·53–0·96, 

 = 0.027). Moreover, 74% (n = 93) of patients in the enzalutamide group experienced overall disease progression compared to 76% of patients in the placebo group. Enzalutamide was also favored vs placebo in patients who also had progression of bone disease and soft tissue disease at 26% vs 27% and 26% vs 33%, respectively. However, more patients had unequivocal clinical progression on enzalutamide, 14%, compared with patients on placebo, 10%, who progressed.

“PRESIDE provides evidence that concomitant administration of enzalutamide and docetaxel might serve as a treatment option for patients who progress on enzalutamide alone,” explained researchers in their assessment of the results.

Ultimately, 271 patients with mCRPC were randomized to either enzalutamide maintenance plus chemotherapy or placebo. Eligible patients had to have histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small-cell features, and serum testosterone concentrations of 1.73 nmol/L or less. These patients also had to have progressed while being treated with androgen deprivation therapy with a luteinising hormone-releasing hormone agonist, antagonist, or after bilateral orchiectomy.

Progression at study entry was defined as either three observed increases in prostate-specific antigen (PSA) concentrations, with 1 week or more between each increase, or a PSA value of 2 ng/mL or greater. Patients were considered to have metastatic disease if at least two bone lesions (assessed by a bone scan) or soft tissue disease (assessed by CT or MRI) were documented. Exclusion criteria included if patients previously used aminoglutethimide, ketoconazole, abiraterone acetate, enzalutamide, or cytotoxic chemotherapy, antiandrogens, 5-α reductase inhibitors, oestrogens, or opiate analgesia 4 weeks before the initiation of enzalutamide.

136 patients were then assigned to enzalutamide and 135 were assigned to placebo with the median age of patients in the treatment arm were 71 years of age and 69 years of age in the placebo arm. In the study arm, 50% of patients had an ECOG performance score of 1 with 50% in the placebo arm having an ECOG score of 0. At diagnosis 56% of patients in the enzalutamide arm had a Gleason score of 8 or higher compared with 57% in the placebo arm. Location of the metastases were either in the bone, soft tissue, or bone and soft tissue in the study arm and placebo arm at 42% vs 35%, 21% vs 18%, and 37% vs 47%, respectively.

The responses for this patient group were favored by patients with enzalutamide, and more so in the overall response rate (ORR) of patients with soft tissue disease at 41% compared with 39% in the placebo group. Enzalutamide was also associated with a significant reduction in risk of PSA progression (HR 0.58; 95% CI, 0.41–0.82, 

 = 0.0021). Moreover, in the enzalutamide group median time to PSA progression was 8.4 months (95% CI, 8.2–9.0) compared with 6.2 months (95% CI, 5.4–8.3) in the placebo group.

“Although the enzalutamide group of PRESIDE had higher levels of serious treatment-emergent adverse events than the placebo group, the overall safety findings of the trial are consistent with those of previous studies,” the researchers noted when looking at the adverse events (AEs) associated with enzalutamide while noting its efficacy in this patient population.

Overall, each study arm had similar total incidences of grade 3 treatment-emergent AEs (TEAEs) at 38% in the enzalutamide arm and 37% in the placebo group, with 24% of patients in the study arm experiencing a grade 4 TEAE compared with 25% in the placebo group. The most common TEAEs in the enzalutamide arm vs placebo arm included neutropenia (13% vs 9%), asthenia (7% vs 4%) and the most common grade 4 TEAE was neutropenia (17% vs 21%). Other notable TEAEs at grades 1-2 in the enzalutamide arm vs placebo arm also included alopecia (30% vs 27%), fatigue (27% vs 18%), and docetaxel related TEAEs (32% vs 36%).

Merseburger AS, Attard G, Åström L, et al. Continuous enzalutamide after progression of metastatic castration-resistant prostate cancer treated with docetaxel (PRESIDE): an international, randomised, phase 3b study. 

 2022 Nov;23(11):1398-1408. doi: 10.1016/S1470-2045(22)00560-5

Results from a phase 3 study show that the continuous maintenance therapy of enzalutamide reduces the risk of disease progression in certain patients with metastatic castration resistant prostate cancer.

Continuous Enzalutamide Proves Beneficial in Previously Treated mCRPC

The use of telisotuzumab vedotin (ABBV-399) plus erlotinib (Tarceva) for patients with c-MET protein expressing non–small cell lung cancer (NSCLC) showed promising antitumor activity, according to results published in the 

Findings from a phase 1/1b study multicenter, open-label study (NCT02099058) of 42 patients with confirmed c-MET overexpression, 

 amplification, in their disease showed that along with promising efficacy results, the combination therapy had an acceptable toxicity profile.

The most common any grade adverse events (AEs) observed by researchers were peripheral sensory neuropathy (43%), dermatitis acneiform (38%), diarrhea (33%), and hypoalbuminemia (33%). Grade 3 or higher AEs occurred in 27 patients with the most common being pulmonary embolism (14%), hypokalemia (10%), diarrhea (7%), malignant neoplasm progression (7%), peripheral sensory neuropathy (7%), and hypophosphatemia (7%).

Any grade treatment-related adverse events (TRAEs) linked to the use of telisotuzumab vedotin were seen in 37 patients, including peripheral sensory neuropathy (36%) and peripheral neuropathy (19%). However, grade 3 or greater TRAEs occurred in 13 patients with the most common also being peripheral sensory neuropathy (7%) and hypophosphatemia (7%).

Other serious AEs related to treatment included decreased appetite, dehydration, hemoptysis, peripheral neuropathy, and pneumonia, among 2% of patients each. Ultimately, the most common AE that led to either dose reductions, interruptions, or discontinuation was peripheral neuropathy at 10%, 21%, and 21%, respectively.

“Although 11 patients [26%] required dose interruption or discontinuation of [telisotuzumab vedotin] because of neuropathy, most of these events were mild-to-moderate, only 12% of grade ≥ 3,” researchers wrote when explaining the acceptable toxicity profile of the drug. “The rate of peripheral sensory neuropathy in this study (43%) was similar to that observed with other approved monomethyl auristatin E [MMAE] antibody drug conjugate-containing drugs.”

Telisotuzumab vedotin is a first-in-class antibody drug conjugate that uses a cleavable linker to combine a recombinant c-Met–targeting humanized monoclonal antibody (ABT-700) and MMAE, which is a potent inhibitor of microtubule polymerization. According to the researchers, by combining this with erlotinib, the treatment allows clinicians to target both c-MET and 

In this study, all enrolled adult patients had been previously treated with tyrosine kinase inhibitors and given 2.7 mg/kg of telisotuzumab vedotin intravenously once every 3 weeks. In the study cohort, 53% were defined as c-MET high with a confirmed histology score greater than 225, while 

 amplification was found in 6 patients. Four patients were positive for 

-wild-type, and 3 patients had a rare/unknown 

 amplifications were also classified as c-Met-high. Thirteen patients were also confirmed to have 

 mutations with 6 patients having c-Met-high mutations and 7 with lower c-Met expression in their NSCLC.

The median duration to exposure to treatment lasted at 18.1 weeks (range, 3.1-99.1) with patients receiving a median of 7 treatment cycles (range, 2-34). Median duration of exposure to erlotinib was 20.3 weeks (range, 3.1-110.4) with patients given a median of 5.5 treatment cycles (range, 2-33).

The objective response rate (ORR) was 30.6% (95% CI, 16.3%-48.1%) for all evaluable patients with a disease control rate (DCR) of 86.1% (95% CI, 70.5%-95.3%). Twenty patients had stable disease, 10 had a partial response, 5 patients had progressive disease, and only 1 patient had a complete response with that patient also having c-Met-positive disease and an 

 mutation-positive disease, the ORR was 32.1% (95% CI, 15.9%-52.4%) with a DCR of 85.7% (95% CI, 67.3%-96%). When looking at patients with 

 mutations, the ORR was 31% and the DCR was 77%. The median progression-free survival in the entire population was 5.9 months (95% CI, 2.8-not reached [NR]) and the duration of response was NR at the time of data cutoff.

“In conclusion, the combination of telisotuzumab vedotin plus erlotinib showed an acceptable safety profile and encouraging antitumor activity in heavily pretreated patients, especially in [

c-Met-positive] NSCLC in which previous EGFR TKIs failed,” the researchers wrote. “Although exploratory, targeting c-Met and 

 showed promising results in this underserved patient population and is worthy of further evaluation in larger studies.”

Camidge DR, Barlesi F, Goldman JW, et al. Phase Ib Study of Telisotuzumab Vedotin in Combination With Erlotinib in Patients With c-Met Protein-Expressing Non-Small-Cell Lung Cancer. 

. 2022 Oct 26:JCO2200739. doi: 10.1200/JCO.22.00739

By combining telisotuzumab vedotin with erlotinib for patients with c-MET protein expressing non–small cell lung cancer, researchers saw promising early antitumor activity.  

Telisotuzumab Vedotin Shows Promising Antitumor Activity in Certain Patients with NSCLC

Treatment with the CAR-T cell therapy tisagenlecleucel (Kymriah) shows promising antitumor activity in young children and infants with B-cell precursor acute lymphoblastic leukemia, according to findings published in 

In an international, multicenter, retrospective cohort study, conducted at 15 hospitals across ten countries in Europe, researchers found that after a median follow-up of 14 months of previously treated patients given tisagenlecleucel overall survival (OS) was 84% (n = 64–93; 5 patients had died), event-free survival (EFS) was 69% (47–83; 9 events), and stringent EFS was 41% (23–58; 18 events). Moreover, the probability of ongoing B-cell aplasia was 70% (95% CI 46–84; 7 events) at 12 months. However, there was no significant association between pre-treatment risk factors and outcome measures.

“Responses were durable in a substantial proportion of patients, with a median event-free survival of 20.3 months. To our knowledge, this is the largest and most comprehensively reported cohort of younger children treated with licensed CD19-targeting CAR T-cell therapy published to date, and the only study to systematically report the use of a licensed CAR T-cell therapy for this indication in this age group,” the researchers wrote.

Of the 28 patients who received an infusion and response could be assessed 86% (n = 24) had a complete response with or without a hematological recovery. All responses were reached by 30 days after the tisagenlecleucel infusion and had been associated with measurable residual disease negativity. Moreover, 7 patients received their infusion after attaining a measurable residual disease-negative bone marrow status after their bridging therapy and without measurable extramedullary disease. Of the 4 patients who did not have a response died of disease progression within 3 months after their infusion.


OS at 6 months in this group was 88% (95% CI, 71%–95%) and at 12 months was 84% (95% CI, 64%-93%) with an EFS rate of 75% (95% CI 56%–87%) at 6 months and 69% (95% CI, 47%–83%) at 12 months. Of the 7 patients who received an infusion and had no measurable residual disease EFS was 100% at 6 months and 12 months, but in comparison, stringent EFS was 83% at 6 months and 67% at 12 months.


Of the 31 patients who received a complete response 8 patients had a disease relapse during follow-up with 2 relapses involving evolution to CD19-negative disease, while one patient had a mixture of CD19-positive and CD19-negative blasts on biopsy of an extramedullary chloroma. However, there were no cases of lineage switch as a cause for emergence of CD-19-negative disease in patients given a tisagenlecleucel infusion, and the other 5 relapses were CD19-postive still.

Fifteen of 35 patients received further therapy during follow-up, but in 6 patients they had a frank relapse either for not responding to CAR T-cell therapy or an early B-cell recovery at 6 months or less after infusion. Four children within the study were aged 1 year or older during their diagnosis, with one child having 

-rearranged disease, and did not receive CAR T-cell infusion due to a manufacturing failure while one child died due to their disease. However, the other 3 children received an infusion of tisagenlecluecel.

The median age of the entire 38-patient cohort was 5.2 months and at the time of tisagenlecleucel infusion the median age was 17 months. Eighty-two percent of patients had been previously treated according to the Interfant-06 protocol and 76% had 

-rearranged ALL. Most patients received previous immunotherapy with 18% receiving previous inotuzumab ozogamicin and 37% had received blinatumomab.

For the patients who received the study drug the median bone marrow blast percentage before lymphodepletion 5%. Twenty-percent had undetectable measurable residual disease, 29% had measurable residual disease that was detectable at up to 5% blasts, and 51% had a disease burden of 5% blasts or more, with 7 patients who had a disease burden of greater than 50% blasts. The study included mostly male patients at 21 patients with 17 female patients.


Regarding safety of this patient population, cytokine release syndrome (CRS) of any grade occurred in 60% (n =21) who received a tisagenlecleucel infusion with grade 3 or worse occurring in 5 patients. The median duration of CRS was 1.5 days in this cohort, with a median duration of ICU stay at 2 days.

Grades 1 or 2 neurotoxicity, or immune effector cell-associated neurotoxicity syndrome, in patients given tisagenlecleucel was seen in 26% of patients, and prolonged cytopenia was observed in 15 patients. Infections were seen in ten of the evaluable patients with most being grade 3 or worse, with 2 cases of febrile neutropenia, but there were no deaths due to toxicity.

“Our findings are encouraging with respect to the historical outcomes of infant acute lymphoblastic leukaemia following HSCT, and, if confirmed with longer follow-up, they support the development of prospective studies to compare the efficacy of tisagenlecleucel against HSCT earlier in the course of therapy in this population,” the researchers concluded.

Ghorashian S, Jacoby E, De Moerloose B, et al. Tisagenlecleucel therapy for relapsed or refractory B-cell acute lymphoblastic leukaemia in infants and children younger than 3 years of age at screening: an international, multicentre, retrospective cohort study. 

. 2022 Oct;9(10):e766-e775. doi: 10.1016/S2352-3026(22)00225-3

The CAR T-cell therapy tisagenlecleucel showed promising anti-tumor activity in pediatric patients with acute lymphoblastic leukemia.