Brielle Benyon

Response rates in patients with metastatic urothelial carcinoma (mUC) were boosted when the novel PI3K-y inhibitor eganelisib (IPI 549) was added to nivolumab (Opdivo), according to recent research presented during the American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium.

“PD-1 inhibitors have demonstrated clinical benefit in metastatic urothelial carcinoma. However, clinical benefit remains low, particularly in PD-L1–low patients, who have [an average] overall response rate of only 16%,” said study author Piotr Tomczak, of the Poznan University of Medical Sciences in Poznan, Poland.

The phase II MARIO-275 study (NCT03980041) included 49 patients with mUC who progressed on 1 or more platinum-based chemotherapy regimens and had no prior treatment with a checkpoint inhibitor. Study participants were stratified by baseline circulating monocytic myeloid suppressor cell (mMDSC) levels and randomized 2:1 to receive eganelisib plus nivolumab or placebo plus nivolumab.

Objective response rate (ORR) per RECIST v1.1 in patients with high baseline mMDSC levels (

22.3) was the primary end point, and researchers also examined overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Duration of exposure was a median of 15 weeks for patients treated with – and 11 weeks for the placebo arm.

While no mMDSC-high patients responded to treatment with eganelisib, there was a higher response rate in the overall population treated with the combination regimen, compared to placebo ([30.3%; 95% CI, 16-9] vs [25%; 95% CI, 7-52], respectively). Additionally, there was a 38.5% ORR in mMDSC-low patients who received eganelisib (95% CI, 20-59), compared to 23.1% in the mMDSC-low patients who received placebo (95% CI, 5-54).

There were 5 PD-L1–positive patients (TPS >1%) in the combination treatment group, of which 4 (80%) responded to the addition of eganelisib to nivolumab (95% CI, 28-100), compared to 2 of 4 (50%) in the placebo group (95% CI, 7-93). In PD-L1–negative patients (TPS <1%) 6 out of 23 patients (26.1%) responded to to the combination regimen (95% CI, 10-48), versus 1 of 7 (14.3%) in the placebo group (95% CI, 0-58).

“The combination demonstrated improved ORR, disease control rates, and PFS when compared to the control, especially in the PD-L1–negative patients, who represent approximately 70% of the patient population,” Tomczak said.

When it came to PFS, 9.1% of patients responded on the combination therapy, compared to 8% on the placebo arm.

Common all-grade adverse events (AEs) in the eganelisib and placebo arms were pyrexia (33% vs 0%, respectively), decreased appetite (30% vs 19%), pruitis (24% vs 6%), asthenia (21% vs 31%), and transaminase elevation (21% vs 6%). The most common grade 3 or higher AEs were hepatotoxicity (15% vs 0%, respectively), transaminase elevation (12% vs 6%), and rash (9% vs 0%). After a safety review, the eganelisib dose was reduced from 40 mg to 30 mg, which lowered the rate of hepatic AEs.

“Importantly, nivolumab monotherapy in the control arm of MARIO-275 demonstrated clinical activity consistent with monotherapy with nivolumab in CheckMate-275, further adding to our confidence in interpreting the contribution of eganelisib [with] nivolumab in the controlled study,” Tomczak said.

Based on these findings, a larger study is being planned in the future to further evaluate eganelisib in PD-L1–low patients.

“Given the magnitude of unmet need in the PD-L1–low patient [population], Infinity is planning a registration and labeling study exploring the potential benefit of eganelisib for PD-L1–low patients, more broadly in other indications,” Tomczak said.

Tomczak T, Popovic L, Barthelemy P, et al. Preliminary analysis of a phase II, multicenter, randomized, active-control study to evaluate the efficacy and safety of eganelisib (IPI 549) in combination with nivolumab compared to nivolumab monotherapy in patients with advanced urothelial carcinoma. Presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021; Virtual. Abstract 436.

Articles

Response rates in patients with metastatic urothelial carcinoma were boosted when the novel PI3K-y inhibitor eganelisib was added to nivolumab, according to recent research presented during the American Society of Clinical Oncology 2021 Genitourinary Cancers Symposium. 

Adding Eganelisib to Nivolumab May Improve Response in Metastatic Urothelial Cancer

Better survival outcomes may occur in patients with non-small cell lung cancer (NSCLC) who experience immune-related adverse events (irAEs), but the presence of certain mutations may interfere with survival , according to research presented at the 2020 World Conference on Lung Cancer.

The analysis specifically showed that patients with STK11 mutations tended to have a shorter progression-free survival (PFS) than those who had STK11 wildtype. In patients who presented with KRAS mutations, STK11 mutations also correlated with a lower 12-month overall survival (OS) rate.

The researchers analyzed the outcomes of patients with stage 3b/4 NSCLC who were tested for the STK11 mutation and were treated with immune checkpoint inhibitors between July 2014 and November 2019. In addition to determining the role of STK11 mutations and if occurrence of irAEs predicted immunotherapy response, the authors also wanted to determine the incidence of STK11 mutations and irAEs among Hispanic and non-Hispanic patients.

The study population included 96 patients who were SKT11 wildtype and 31 with an SKT11 mutation, both groups had a median age of 65 at diagnosis. Forty-eight patients experienced an irAE (median age, 70 years) and 77 patients were irAE-negative (median age, 66 years). Overall, there were 30 Hispanic patients involved: 8 harbored the SKT11 mutation, and 14 experienced an irAE.

STK11-Mutant Versus SKT11 Wildtype Outcomes

Median OS was higher in STK11 wildtype patients than it was in STK11-mutant patients (12.1 months versus 8.6 months, respectively; 

= 0.03). Twelve-month OS was also higher with the wildtype group (73% versus 55%; 

=0.03). Patients with an STK11 wildtype did have a slightly higher median PFS (6.3 months versus 5.6 months) and 12-month PFS (45% versus 43%), though those findings were not statistically significant (

When it came to STK11 and KRAS mutations together, patients with STK11 wildtype had a higher rate of 12-month OS than those with the STK11 mutation (70% versus 40%, respectively, 

However, the OS findings were not statistically significant (11.4 months versus 5.3 months; 

=0.13), nor were PFS findings in the KRAS-mutant group. Median PFS in the SKT11 wildtype group was 5.1 months and in the SKT11 group was 3 months.

Patients who experienced an irAE had statistically significant better PFS and OS outcomes.

Average PFS was 9.5 months in those who had an irAE, compared to 4.4 months in those who did not (

=0.005). Twelve-month PFS was also better in those who had an irAE than those who didn’t (60% versus 33%, respectively; 

When it came to OS, average OS was 14.2 months in the irAE-positive group and 7.3 months in the irAE-negative group (

<0.001). Twelve-months OS was also higher in the group who had an irAE, at 85%, compared to those who did not, 60% (

The most common irAEs were hypothyroidism, which was experienced by 35.7% of Hispanic irAE-positive patients and 14.7% of non-Hispanic irAE patients; rash (21.4% and 29.4%); and pneumonitis (7.1% and 5.9%).

The authors note the results indicate that the occurrence of irAEs may be useful in identifying possible responders to therapy. Therefore, they ask providers to monitor and manage those events carefully to maximize whatever benefits may come from therapy while also reducing risks.

They also mentioned that their findings should be further evaluated in larger studies in the future.

Raez Le, Uba R, North A, et al. STK11/LKB1, KRAS mutations and immune-related adverse events as predictors of response to immunotherapy in lung cancer. Presented at: 2021 World Conference on Lung Cancer Singapore, January 28-31, 2021.

A correlation between the emergence of immune-related adverse events and presence of mutations was identified in patients with non-small lung cancer receiving immunotherapy. 

Presence of Mutations and Emergence of irAEs May Correlate With I/O Response in NSCLC

Patients with epithelial ovarian cancer treated with weekly dose-dense chemotherapy in the ICON8 clinical trial experienced similar progression-free survival (PFS) and overall survival (OS) as patients treated with the standard-of-care (SOC), demonstrating that weekly dose-dense chemotherapy is not superior of SOC in this population, according to a presentation at the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.

Weekly dose-dense chemotherapy is not superior to standard 3 weekly chemotherapy for patients with epithelial ovarian cancer when it comes to progression-free survival (PFS) and overall survival (OS), though the regimen is safe and effective, according to results from the ICON8 study presented at the ESMO Virtual Congress 2020.1

“[For] the most of the last 3 decades, platinum paclitaxel doublet chemotherapy administered on a once every 3 week schedule for 6 to 8 cycles has been cornerstone in the first-line modality management of epithelial ovarian cancer,” said chief investigator Andrew Clamp, BMBCh, senior lecturer and honorary consultant in medical oncology at the Christie NHS Foundation Trust.

ICON8 included 1566 patients with epithelial ovarian cancer who had FIGO stage IcG3-IV disease. Participants were randomized 1:1:1 to 3 arms:

Arm 1, standard chemotherapy, q3w carboplatin AUC5/6 plus q3w paclitaxel 175 mg/m

Arm 2, weekly paclitaxel (q3w carboplatin AUC5/6 plus q1w paclitaxel 80mg/m2 (n=523)

Arm 3, weekly carboplatin-paclitaxel (q1w carboplatin AUC2 plus q1w paclitaxel 80 mg/m

“There’s a strong rationale for the evaluation of weekly dose paclitaxel after settling in to the first line of treatment,” Clamp said, citing preclinical animal evidence of metronomic taxane treatment could improve drug delivery, increase tumor cell apoptosis, and reduce angiogenesis.

Baseline characteristics were well balanced among the arms. The median age of study participant was 62; 72% had serous histology; 10.5% were stage Ic-IIa; 18% were stage IIa-IIIb; and 71% were stage IIIc-IV. Half (50%) of patients planned delated primary surgery (DPS), while slightly less (48%) had immediate primary surgery (IPS). Two percent of patients were inoperable.

As of October 1, 2019, median OS was 47.4, 54.1, and 53.4 months in arms 1, 2, and 3, respectively. There were 319 deaths in arm 1 (61%), 300 deaths in arm 2 (57%), and 304 deaths in arm 3 (58%). There was no significant improvement in OS comparing arm 2 versus arm 1 (97.5% CI, 0.74-1.06; p=.14, HR =.88); arm 3 versus arm 1 (97.5% CI, 0.76-1.09; p=0.27, HR=0.91).

Median time to progression was 25, 25.5, and 25.9 months in arms 1, 2, and 3, respectively, again showing no statistically significant difference (arm 2 versus arm 1 p=0.37; arm 3 versus arm 1 p=0.48).

The toxicity profile of the weekly regimen was previously presented at the ESMO annual meeting in 2017, and Clamp said that there were no changes in adverse events.

“The two weekly treatment arms were associated with an increased incidence of any grade 3 or 4 events during treatment, but this was predominantly driven by uncomplicated growth [grade] 3 or 4 neutropenia,” Clamp said. “Reassuringly, incidence of febrile neutropenia was low in all 3 treatment arms, and we did not see any increase of grade 2 or more sensory neuropathy in the 2 weekly dose-dense paclitaxel-containing regimen.”

Ultimately, Clamp explained that since the dose-dense regimen did not show improved survival results, weekly paclitaxel can remain standard of care for this patient population, though more research is needed.

“Other further hypothesis-generating analyses are underway in our DPS cohort to determine if there is a subgroup of patients who may benefit with the more dense approach,” Clamp said.

Clamp AR, James EC, McNeish I, et. al. ICON8: overall survival results in a GCIC phase III randomized controlled trial of weekly dose-dense chemotherapy in first line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment. Presented at: ESMO Virtual Congress 2020, Sept. 19-21, 2020. Accessed Sept. 21, 2020.

Patients with epithelial ovarian cancer treated with weekly dose-dense chemotherapy in the ICON8 clinical trial experienced similar progression-free survival and overall survival as patients treated with the standard-of-care.

Non-Superiority of Weekly Dose-Dense Chemotherapy Versus SOC Shown in Epithelial Ovarian Cancer

Teclistamab (JNJ-64007957) may be a safe and efficacious treatment option for patients with relapsed/refractory multiple myeloma, according to findings from a phase I study presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

Another treatment option would be a welcome change for these patients, who tend to have poor prognoses once they run out of treatment options, according to Saad Z. Usmani, MD. After becoming refractory to available therapies, median overall survival (OS) is 6-11 months.

“Multiple myeloma is a complex disease, and despite recent advances with new therapies, patient outcomes are poor once available classes of therapies are exhausted,” Usmani, chief of the Plasma Cell Disorders Program and director of Clinical Research in Hematologic Malignancies at the Levine Cancer Institute, Atrium Health, said while presenting the findings.

The study (NCT03145181) involved 78 patients with relapsed/refractory myeloma who received teclistamab – a bispecific duo antibody that binds to BCMA and CD3 – intravenously. Median age was 64 years old (range, 24-82), and the median number of prior therapies was 6 (range, 2-14). Overall, 72% of participants were triple-class exposed, 62% triple-class refractory, and 51% penta-drug refractory.

Part 1 of the study was a dose-escalation trial, with a primary objective of finding the doses for part 2. Doses ranged from 0.3-720 µg/kg weekly, and there was a 67% overall response rate (ORR; 50% ≥ VGPR) at 270 µg/kg.

“Response rates increased with higher doses of teclistamab,” Usmani said.

The drug became active in patients receiving 38.4 µg/kg or higher, with 21 out of 52 patients (38%) achieving a response, per IMWG criteria. Two patients were minimal residual disease (MRD)-evaluable per next-generation sequencing, and they both were MRD negative at 10-6 with treatment ongoing > 12 months.

“Looking at the durability of response, we concluded that the responses deepened over time,” Usmani said, noting that 16 of the 21 patients who responded have an ongoing response.

The most common adverse events (AEs) of all grades were cytokine release syndrome (CRS; 56%), neutropenia (26%), and anemia (23%). CRS typically occurred during the initial doses, and all CRS events were grade 1-2. Additionally, 8% of patients experienced a treatment-related neurotoxicity (grade 3 or higher, 3%) and 9% had an infusion-related reaction.

A total of 61% of patients experienced an infection-related AE with 21% of them being grade 3 or higher. Reported dose-limiting toxicities were delirium (which was resolved after 16 days) and thrombocytopenia (resolved after 1 day).

More than a third of patients (36%) had ≥3 AE, with neutropenia and anemia being the most frequent, occurring in 20% and 14% of patients, respectively. One grade 5 AE was reported and was respiratory failure in the setting of pneumonia that the investigator deemed unrelated.

“Intermittent dosing is viable based on these data … teclistamab was manageable across all doses,” Usmani said.

Efficacy data at the 720 µg/kg dose are not yet mature, and the dose escalation and expansion phases of the trial are still ongoing, Usmani explained. Future findings could lay the groundwork for a promising new therapy for this patient population.

“BCMA and CD3 bispecific antibody approaches offer an off-the-shelf, immune-mediated therapy for these patients,” Usmani said.



Usmani SZ, Mateos M, Nahi H, et. al. Phase I study of teclistamab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM). Presented at: 2020 ASCO Virtual Scientific Program. May 29-31, 2020. Abstract 100.

<< View more of Targeted Oncology's coverage from the 2020 ASCO Virtual Annual Meeting

Another treatment option would be a welcome change for these patients, who tend to have poor prognoses once they run out of treatment options, according to Saad Z. Usmani, MD. After becoming refractory to available therapies, median overall survival is 6-11 months.

Brielle Benyon | Authors

Articles

Adding Eganelisib to Nivolumab May Improve Response in Metastatic Urothelial Cancer

Presence of Mutations and Emergence of irAEs May Correlate With I/O Response in NSCLC

Non-Superiority of Weekly Dose-Dense Chemotherapy Versus SOC Shown in Epithelial Ovarian Cancer

Teclistamab Appears Safe, Efficacious in Relapsed/Refractory Multiple Myeloma