Silas Inman

Enlarged spleen is a common symptom of myelofibrosis, but a new regimen of navitoclax and Jakafi may help, recent findings showed.

The combination of navitoclax with Jakafi (ruxolitinib) reduced spleen volume by 35% or more at week 24 when being compared with Jakafi in combination with placebo for patients with myelofibrosis, according to findings from the phase 3 TRANSFORM-1 study that were presented at the 2023 

American Society of Hematology (ASH) Annual Meeting and Exposition

After a median follow-up of 14.9 months, navitoclax and Jakafi resulted in a spleen volume reduction of 35% or more by week 24 for 63.2% of patients compared with 31.5% for placebo plus Jakafi, marking a significant overall difference of 31%. At week 24, there was an average -9.7 change in TSS (total symptom score) with navitoclax/ Jakafi from baseline compared with a change of -11.1 for placebo plus Jakafi, which was not statistically significant.

“The spleen volume reduction was doubled and highly statistically significant. There’s no question there, but for the secondary end point, the total symptom score, both groups have the reduction, but it was not statistically significant,” said lead investigator Dr. Naveen Pemmaraju, Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “There may be multiple reasons for that. (Jakafi) alone is a nice drug for symptom improvement, but when you add in a second drug, you're improving the outcomes for the patient but maybe introducing a bit more toxicity. The statistical significance may not have come out because of that.”

Oral Jakafi is a drug that inhibits certain proteins (BCL-XL, BCL-2 and BCL-W), which may impart unique efficacy for myeloproliferative neoplasms (MPN).

“It turns out in MPN and myelofibrosis that the BCL-XL pathway appears to be a bit more important than the BCL-2,” said Pemmaraju. “In myelofibrosis, BCL-XL appears to be upregulated and so in vitro studies showed that either the Jakafi by itself or even better in combination with the Jakafi can overcome JAK resistance and add benefit.”

The median TSS in the combination arm was 21 compared with 24 in the control group. A minority of patients were transfusion dependent at baseline, at 4% in the combination group and 3% in the control arm. The most common risk score was intermediate-2, at 83% in the combination group and 87% in the control. JAK2 V617F was the most common driver mutation, with approximately two-thirds having this mutation in each group. Nearly half of patients had mutations associated with high molecular risk. “These high molecular risk mutations are very important,” said Pemmaraju. “Earlier studies may not have captured this, and we were fortunate to capture this in the majority of patients.”

There was a significantly higher rate of spleen volume reduction of 35% or more with the combination at all time points throughout the study. Across the full-time scale of the study, 76.8% of those in the combination arm experienced a spleen volume reduction of at least 35% compared with 41.7% with Jakafi in combination with placebo, which was a meaningful 34.6% reduction.

The median time to first spleen volume reduction of 35% response was similar between groups, at 12.3 vs 12.4 weeks, for the combination and control arms, respectively. Fewer patients lost spleen volume reduction of 35%, in the combination group (18.8%) compared with the control arm (26.4%). Nearly three-fourths of patients had a 12-month duration of spleen volume reduction of 35% in each arm (76.7% vs 76.9%, combination and control, respectively).

The rate of any-grade side effect was similar between arms, with more patients in the combination arm having a grade 3 or higher side effect (85% vs 70%). The most common grade 3 or higher side effects in the combination vs control arms, respectively, were thrombocytopenia (51% vs 15%), anemia (46% vs 39%) and neutropenia (38% vs 4%). For all grade events, diarrhea was more commonly seen with the combination vs control (34% vs 14%). Serious side effects were less common with the combination at 26% compared with 32% for the control arm. Side effects that led to dose reduction or dose interruption were twice as common in the combination arm.

“Importantly, dose reductions and interruptions were mostly due to the thrombocytopenia, but importantly none of those were due to clinical bleeding,” said Pemmaraju.

In 2022, AbbVie, the company developing navitoclax noted plans for a submission to the FDA in 2023, pending pivotal study results.

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The recent phase 3 TRANSFORM-1 study concluded that navitoclax combined with Jakafi showed significant spleen volume reductions in patients with myelofibrosis.

Navitoclax Plus Jakafi Improves Spleen Volume Reductions in Myelofibrosis

Patients with grade 2 IDH-mutant glioma experienced a 61% reduced risk of progression or desk when treated with vorasidenib. 

Patients with grade 2 IDH-mutant glioma (a type of brain cancer) experienced a 61% reduced risk of progression or desk when treated with vorasidenib (AG-881) compared with placebo, according to results from the phase 3 INDIGO clinical trial, presented at the 2023 

Progression-free survival (time from treatment until disease progression) with vorasidenib was 27.7 months compared with 11.1 months for those treated with placebo. Treatment in the study was given during a “watch and wait” period used to delay the start of debilitating chemoradiation therapy, which is standard following glioma resection. In addition to improvements in progression-free survival, vorasidenib also resulted in a significant lengthening in the interval to receipt of another treatment.

 mutations with vorasidenib significantly delays tumor growth and the need for more toxic therapies,” lead author Dr. Ingo Mellinghoff, of Memorial Sloan Kettering Cancer Center, said in a statement. “This is clinically meaningful because patients diagnosed with grade 2 glioma with 

 mutations are typically young, otherwise healthy individuals. The results of this trial offer a chance to change the treatment paradigm for this type of glioma and could bring the first new targeted therapy for low-grade glioma.”

In the study, 331 patients were randomly assigned to receive oral vorasidenib (168 patients) at 40 mg once daily or matched placebo (163 patients) in 28-day cycles.

Histologic subtypes of low-grade glioma were evenly distributed between oligodendroglioma and astrocytoma. The location of the tumor at primary diagnosis was frontal for two-thirds of patients. The longest diameter of tumor was 2 or more centimeters for most patients (82.7% vs 84.0%, for vorasidenib and placebo, respectively). The median interval from last glioma surgery to randomization was 2.4 years and 21.5% had received 2 or more tumor surgeries before enrollment.

 alteration, which was present in 97% of those in the vorasidenib arm and for 93.3% in the placebo group. More than half of patients also had a codeletion in chromosome 1p/19q.

The median follow-up was 14 months for vorasidenib and was 14.3 months for placebo. Progression occurred in 28% of those in the vorasidenib arm compared with 54% for those in the placebo group. Investigator-assessed results were similar to those reported in the primary analysis, with vorasidenib remaining superior.

There was an 85.6% likelihood of not requiring another intervention at 18 months in the vorasidenib arm compared with 47.4% in the placebo arm. At the 24-month assessment, 83.4% of patients in the vorasidenib arm still had not required another intervention compared with 27% in the placebo group. Following initial results, the study was unblinded and patients were allowed to cross over. There were 52 patients initially in the placebo arm (31.9%) who crossed over to receive vorasidenib.

“Second interim analysis was so clear and showed efficacy so clearly that the data monitoring board recommended that we unblind,” Mellinghoff noted.

The 18-month progression-free survival rate was 60.4% in the vorasidenib group compared with 26.7% in the placebo group. The 24-month progression-free survival rates were 50.7% in the vorasidenib arm compared with 17.6% in the placebo group.

The objective response rate (percentage of patients whose disease shrunk as a result of treatment) was 10.7% with vorasidenib compared with 2.5% for placebo. In the vorasidenib group, this included two partial responses (1.2%) and 16 minor responses (9.5%). The placebo arm was all minor responses. Most patients had stable disease, with progressive disease seen in 6.0% and 8.6% of those in the vorasidenib and placebo arms, respectively.

An ASCO Expert commenting on the results, Dr. Glenn Lesser, said “These results are quite striking and they’re statistically highly significant, and more important, they’re clinically very important. In select patients with low-grade glioma, we can potentially delay the use of these toxic chemotherapy and radiation for years, perhaps many years, and delay the toxicity.”

Side effects of any grade occurred in 94.6% of those in the vorasidenib group and for 93.3% of those in the placebo group. Grade 3 or higher (moderate to severe) side effects occurred in 22.8% of patients in the vorasidenib arm compared with 13.5% of those in the placebo arm. The most common side effects in the vorasidenib arm were related to liver enzyme increases, including increases in alanine aminotransferase (ALT; 38.9%; 9.6% was grade 3 or higher), aspartate aminotransferase (AST; 28.7%; 4.2%), and gamma-glutamyl transferase (GGT; 15.6%; 3.0%).

There were 3 serious side effects reported in the vorasidenib arm that were reported to be associated with the treatment, specifically ALT increase, liver failure and hepatitis. All serious side effects were considered resolved at the time of the analysis in September 2022. Side effects led to discontinuation for 3.6% of patients in the vorasidenib arm compared with 1.2% in the placebo arm. Dose reductions were needed for 10.8% of those in the vorasidenib arm compared with 3.1% in the placebo group. Dose interruptions occurred for approximately one-quarter of patients in both arms.

Vorasidenib reduced the risk of disease progression or death for certain patients with low-grade brain cancer, recent study results showed. 

Vorasidenib May ‘Change the Treatment Paradigm’ for Low-Grade Glioma

The 24-month event-free survival rate was 62.4% with Keytruda plus chemotherapy and adjuvant Keytruda compared with 40.6% for placebo plus chemotherapy.

Adding Keytruda (pembrolizumab) to pre-surgical chemotherapy and then again after surgery led to improvements in outcomes for patients with early-stage non-small cell lung cancer (NSCLC), according to findings from the phase 3 KEYNOTE-671 study presented at the 2023 ASCO Annual Meeting and simultaneously published in the 

In particular, this Keytruda regimen improved event-free survival, which is the time a patient lives without complications from the disease, as well as pathological complete response, which is when cancer is unable to be found on biopsy samples taken during surgery or after treatment.

In the double-blind study, the 24-month event-free survival rate was 62.4% with Keytruda plus chemotherapy and adjuvant Keytruda compared with 40.6% for placebo plus chemotherapy. The major pathologic response rate was 30.2% with Keytruda compared with 11.0% with placebo. The pathological complete response rate was 18.1% with Keytruda compared with 4.0% for placebo. Overall survival data were immature at the time of the analysis, with a 24-month overall survival rate of 80.9% observed in the Keytruda arm compared with 77.6% in the placebo arm.

“Neoadjuvant (Keytruda) plus chemotherapy followed by surgery and adjuvant (Keytruda) provided statistically significant, clinically meaningful improvement in (event-free survival) compared with neoadjuvant chemotherapy and surgery alone,” said lead investigator Dr. Heather Wakelee, from Stanford University School of Medicine and the Stanford Cancer Institute. “Data support perioperative (Keytruda) as a promising new treatment option for patients with resectable stage 2, 3A or 3B NSCLC.”

In the KEYNOTE-671 trial, patients were randomly assigned to receive chemotherapy plus Keytruda (397 patients) or placebo (399 patients). Keytruda was administered at 200 mg intravenously every three weeks in the neoadjuvant setting for four cycles and the adjuvant setting for 13 cycles. Chemotherapy was administered every three weeks and consisted of cisplatin plus either pemetrexed for nonsquamous histology or gemcitabine for those with squamous histology. Every three weeks, cisplatin was administered at 75 mg/m2, pemetrexed at 500 mg/m2, and gemcitabine at 1000 mg/m2 on days 1 and 8.

Baseline patient characteristics were balanced between groups. In the Keytruda group, the median age was 63 years, 70.3% were male, and the ECOG performance status was 0, meaning that there were little to no limitations to daily activities (63.7%) or 1 (36.3%). Two-thirds of patients were White (63%) and 31.2% were Asian, primarily from non-East Asian countries (69.0%). Histology was balanced at 56.9% nonsquamous and 43.1% squamous. A quarter of patients were current smokers (24.2%) and 13.6% were never smokers. The disease stage at baseline was most commonly 3A (54.7%) followed by stage 2 (29.7%), with the remainder being stage 3B (15.6%). Nearly half of patients had N2 disease (42.3%), with the remainder having N1 (20.4%) or N0 (37.3%).

PD-L1 status by tumor proportion score was balanced with a 33.2% having PD-L1 expression of 50% or greater and 34.8% having less than 1% expression of PD-L1. Those with known driver mutations were included in the trial, with 3.5% of tumors harboring an 

 alteration. Driver mutation status was unknown for approximately two-thirds of patients.

Of the patents who entered the neoadjuvant phase, 87.4% completed three or more cycles of treatment in the Keytruda arm compared with 87.2% in the placebo group. There were 342 patients in the Keytruda arm who proceeded to surgery, compared with 335 in the placebo group, with 325 actually undergoing surgery in the Keytruda arm and 317 in the placebo group. Of those who underwent surgery, 290 received 1 or more doses of adjuvant therapy in the investigational arm compared with 267 in the placebo group. Slightly more than one third completed 13 cycles of adjuvant therapy in the Keytruda arm (40.4%) compared with 35.4% in the placebo group. Adjuvant therapy was ongoing for 10.6% and 11.3% of patients, in the investigational and control arms, respectively.

There were more complete R0 resections (complete remissions or cure) in the Keytruda arm compared with the placebo group, with 92.0% of patients receiving an R0 resection in the PD-1 inhibitor arm compared with 84.2% in the placebo group. Incomplete R1 resections occurred in 5.2% and 9.8% of patients in the Keytruda and placebo groups, respectively. The most common type of surgery was a lobectomy, which occurred in 78.8% of patients in the Keytruda arm and 75.1% in the placebo group.

The median follow-up at the July 29, 2022, data cutoff was 25.2 months. At this point, 35.0% of patients in the Keytruda arm had experienced an event, defined as local progression, progression, recurrence or death. In the placebo arm, 51.3% of patients had experienced an event. The median event-free survival was not yet reached with Keytruda compared with 17.0 months for the placebo group.

Event-free survival was consistently improved across subgroups, Wakelee noted, including those with driver mutations. She drew attention to a few key groups, noting that outcomes were similar by histology, PD-L1 expression level, and stage.

At the time of the data cutoff, 19.1% and 25.3% of patients had died from any cause in the Keytruda and placebo arms, respectively. The median overall survival was not yet reached for those in the Keytruda group compared with 45.5 months for the placebo group.

“The KEYNOTE-671 trial and other perioperative immunotherapy studies represent a major advance as new standards of care for the treatment of resectable lung cancer,” said ASCO discussant Dr.Mark M. Awad, from Harvard Medical School and the Dana-Farber Cancer Institute. “Although data are immature, there appears to be an encouraging signal for (overall survival) benefit favoring the neoadjuvant with or with adjuvant immunotherapy approach.”

“Neoadjuvant immunotherapy leads to high rates of mPR and pCR in a variety of solid tumors, and mPR and pCR after neoadjuvant immunotherapy are associated with excellent outcome,” said commenter Dr. Myriam Chalabi, from the Netherlands Cancer Institute. “De-escalation of systemic therapy, less extensive surgery, and omission of surgery are realistic options to consider.”

Treatment-related side effects were similar between treatment groups, with grade 3 to 5 events experienced by 44.9% of patients in the Keytruda group and 37.3% of those in the placebo group. Serious side effects were experienced by 17.7% and 14.3%, respectively. The most pronounced side effects differences were observed for immune-mediate side effects, including infusion reactions, Wakelee noted. Immune-mediate side effects occurred in 25.3% of patients treated with Keytruda compared with 10.5% in the placebo group. There was one death related to an immune-mediate side effect in the Keytruda arm. Immune-mediate side effects ed to Keytruda discontinuation for 5.1% of patients.

The most common side effects were those frequently associated with platinum-based chemotherapy, Wakelee said. These include nausea, neutropenia, anemia, leukopenia and fatigue. The most common all-grade, immune-mediate side effects for pembrolizumab and placebo, respectively, were hypothyroidism (11.1% vs 1.8%), hyperthyroidism (5.6% vs 3.3%), and pneumonitis (5.6% vs 1.8%).

“The (side effect) profile was as expected, based on the known profiles of the individual treatment components,” Wakelee said.

Merck, the developer of pembrolizumab, has already submitted a supplemental new drug application to the FDA, based on findings from the KEYNOTE-671 study. The proposed indication is for the treatment of patients with resectable stage 2, 3A or 3B NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment and continued as a single agent as adjuvant treatment. The FDA is expected to make a decision on the application by Oct. 16, 2023.

Adding Keytruda to pre-surgical chemotherapy then giving it again after surgery improved event-free survival and pathologic complete response in patients with early-stage lung cancer. 

Pre- and Post-Surgical Keytruda Boosts Outcomes in Early NSCLC

The risk for disease progression or death was reduced by 35% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who were treated with Brukinsa (zanubrutinib) compared with Imbruvica (ibrutinib), according to recent study findings.

Results from the phase 3 ALPINE study were presented at the 2022 ASH Annual Meeting and simultaneously published in the 

The 24-month progression-free survival (time from treatment until disease worsens) rate was 79.5% with Brukinsa compared with 67.3% with Imbruvica. The objective response rate (percentage of patients whose disease shrunk as a result of treatment), which was the primary focus of the study, was 86.2% with Brukinsa compared with 75.7% for Imbruvica.

There were fewer side effects that led to treatment discontinuation observed with Brukinsa (15.4%) versus Imbruvica (22.2%). Atrial fibrillation/flutter (heart rhythm abnormalities) was significantly less common with Brukinsa (5.2%) versus Imbruvica (13.3%). There were no fatal cardiac events reported with Brukinsa compared with six events in the Imbruvica group.

“ALPINE is the first study to demonstrated (progression-free survival) superiority in a head-to-head comparison of BTK inhibitors in patients with relapsed or refractory CLL or SLL. (Brukinsa) has now proven superiority to (Imbruvica) in both (progression-free survival) and (objective response rate),” lead study author Dr. Jennifer R. Brown, from the Dana-Farber Cancer Institute in Boston, said during a presentation of the results. “(Brukinsa) has a better cardiac profile than (Imbruvica), with lower rates of atrial fibrillation, serious cardiac events, cardiac events leading to treatment discontinuation and fatal cardiac events.”

In the ALPINE study, 652 patients with relapsed or refractory CLL/SLL were randomized to receive Brukinsa (327 patients) or Imbruvica (325 patients).

Fifty-three patients in this group discontinued due to side effects and 24 discontinued due to progressive disease. In the Imbruvica arm, one patient did not receive treatment, 74 discontinued due to side effects and 42 discontinued due to progressive disease.

After 29.6 months of follow up, the median PFS was not yet reached in the Brukinsa arm compared with 35 months with Imbruvica. In patients with del(17p) or 

 mutations (75 patients in each arm), the 24-month progression-free survival rates were 77.6% versus 55.7% for Brukinsa and Imbruvica, respectively. Progression-free survival favored Brukinsa across other major subgroups analyzed.

A side effect of any grade or cause was experienced by 98.1% of patients in the Brukinsa group and by 99.1% of those in the Imbruvica group. Severe to fatal side effects were seen in 67.3% of those treated with Brukinsa, with 10.2% of patients having fatal side effects. In the Imbruvica group, 70.4% of patients experienced a severe to fatal side effect, with fatal events seen in 11.1% of patients. 

Serious side effects were experienced by 42% and 50% of patients in the Brukinsa and Imbruvica groups, respectively.

The median treatment duration was 28.4 months with Brukinsa versus 24.3 months for Imbruvica. Side effects led to a dose reduction for 12.3% of those in the Brukinsa arm and for 17% of those in the Imbruvica group. Dose interruptions were required due to side effects in 50% and for 56.8% of patients in the Brukinsa and Imbruvica arms, respectively.

Heart-related side effects were experienced by 21.3% and 29.6% of those in the Brukinsa and Imbruvica groups, respectively. Serious heart-related side effects were experienced by six patients in the Brukinsa group (1.9%) compared with 25 in the Imbruvica group (7.7%). Of these patients, two in the Brukinsa group and 16 in the Imbruvica group had no previous cardiac-related medical history.

“Overall, safety was improved with (Brukinsa), with serious (side effects) reduced with (Brukinsa), and (side effects) leading to dose reduction, dose interruption and discontinuation lower with (Brukinsa) versus (Imbruvica),” Brown said.

Progression-free survival and overall response rates greatly improved in patients with CLL/SLL treated with Brukinsa compared with Imbruvica. 

Silas Inman

Navitoclax Plus Jakafi Improves Spleen Volume Reductions in Myelofibrosis

Vorasidenib May ‘Change the Treatment Paradigm’ for Low-Grade Glioma

Pre- and Post-Surgical Keytruda Boosts Outcomes in Early NSCLC

Survival and Treatment Response May Be Further Improved With Brukinsa Versus Imbruvica for CLL/SLL

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