The addition of the investigational anti-CD39 antibody TTX-030 to frontline treatment with the PD-L1 inhibitor budigalimab and mFOLFOX6 was determined to be safe and tolerable in patients with locally advanced or metastatic HER2-negative gastroesophageal junction (GEJ) adenocarcinoma, according to phase 1 findings recently presented at the 2022 AACR Annual Meeting. 

Moreover, the agent produced encouraging antitumor activity in patients, including those with PD-L1 low tumors with a combined positive score (CPS) less than 5.

Investigators also observed that the combined therapeutic was linked to an increase of PD-L1 and CD8 T cells.

Overall, TTX-030 as monotherapy or in combination was not associated with any reported drug-limiting toxicities, and the maximum-tolerated dose of TTX-030 alone was also undetermined. Based on these data, investigators determined that TTX-030 can be safely combined with FOLFOX and anti–PD-1 agents and administered to patients, so long as there are no excessive or synergistic toxicities.

In the total evaluable population (n = 40), the confirmed overall response rate (ORR) was 52.5%. A total of 4 patients experienced a complete response (CR; 10%) and 17 patients experienced a partial response (PR; 42.5%). Sixteen patients (40%) achieved stable disease (SD) and the disease control rate was 92.5% (n = 37), and 3 patients (7.5%) experienced disease progression.

In a subgroup of patients with a CPS score less than 1 (n = 11), the confirmed ORR was 36.4%, compared with 66.7% in those with a CPS score between 1 and 5. In patients whose CPS score as at least 5, the ORR was 64.3%.

“TTX-030 in combination with budigalimab and modified FOLFOX6 for the treatment of patients with HER2-negative metastatic gastric cancer was well tolerated without excessive toxicities,” Zev A. Wainberg, MD, professor of medicine at University of California, Los Angeles (UCLA), and co-director of the UCLA GI Oncology Program, said in a presentation of the findings. “It revealed promising antitumor activity, including in patients [with] PD-L1 tumor CPS less than 5, [and] induced intertumoral increases in PD-L1 expression and CD8 eight cells. These results support further evaluation of TTX-030 combination treatment in patients with metastatic gastric cancer.”

TTX-030 is the first fully human IgG4 antibody designed to target CD39, as well as the first CD39 agent to undergo a phase 1 trial. The non-competitive allosteric inhibitor of CD39 ectoenzyme enzymatic activity functions by binding and inhibiting CD39 at sub-nanomolar potencies in an environment with high extracellular ATP. In doing so, the agent increases extracellular ATP and consequently prevents the generation of adenosine.

“The blockade of CD39 is the first step involved in [the] process by which extracellular ATP is converted to ANP,” explained Wainberg. “The value of that is twofold because first [there is] suppression of adenosine, which is an immunosuppressive agent, along with the maintenance and increased production in essence of extracellular ATP; extracellular ATP has the advantage of activating an innate immune function. Therefore, we have this dual strategy behind blockade CD39.”

In this study, patients with a histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction with HER2-negative disease were enrolled to receive a 28 day-cycle of mFOLFOX6, budigalimab, and TTX-030.

To enroll, patients could not have received prior treatment for metastatic disease, nor could they have received neoadjuvant or adjuvant therapy within 6 months of trial enrollment. The study’s coprimary end points were safety and tolerability, while secondary end points included progression-free survival and ORR, per RECIST/iRECIST criteria.

In the dose-escalation and expansion phases, TTX-030 monotherapy doses ranged from 0.5 to 4.0 mg/kg every 3 weeks. The recommended phase 2 dose (RP2D) was determined to be a 40 mg/kg loading dose 7 days before day 1 of cycle 1. Once the cycle began, the RP2D was 20 mg/kg every 2 weeks.

The median age of patients was 61 years (range, 30-81), and 41% of patients were female; 57% of patients were Asian and 93% of patients were of non-Hispanic or Latino ethnicity. Most patients (61%) had an ECOG performance status of 1. Sixty-eight percent of patients had gastric adenocarcinoma, and the median number of prior therapies was 1.

Treatment is ongoing in 59.1% of patients, and the median time on study was 214 days (range, 8-464).

Overall, 11 patients (25%) experienced at least 1 grade 3 or greater adverse event (AEs) related to budigalimab, and 9 patients (20.5%) experienced at least 1 grade 3 AE related to TTX-030. Twenty-eight patients (63.6%) experienced at least 1 grade 3 AE regardless of relatedness. The most common AEs overall included increased gamma-glutamyl transferase (4.5%), hyperglycemia (4.5%), and deceased neutrophil count (34.1%), hyperglycemia (6.8%), febrile neutropenia (4.5%), and gastric perforation (4.5%).

“Many of us are aware [that] in the last 2 years, we have seen changes in the landscape of the treatment of metastatic gastric cancer, in which the addition of a PD-1 inhibitor, nivolumab, has been approved for patients with metastatic gastric cancer with chemotherapy,” explained Weinberg. “The important point there is that the advantage of the drug is [most prominent] in patients with PD-L1 CPS greater than 5. In the group of patients with a low PD-L1 score, [or a score] under 5, there is a lot of debate [regrading] the value of the addition of nivolumab.”

Investigators are also evaluating the combination as a potential treatment for patients with pancreatic cancer.

Wainberg ZA, Kang YK, Lee KW, et al. Efficacy and safety of TTX-030, an anti-CD39 antibody, in combination with chemoimmunotherapy for thefirst-line treatment of locally advanced or metastatic gastric/GEJ cancer. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT015.

Articles

The addition of the investigational anti-CD39 antibody TTX-030 to frontline treatment with the PD-L1 inhibitor budigalimab and mFOLFOX6 was determined to be safe and tolerable in patients with locally advanced or metastatic HER2-negative gastroesophageal junction adenocarcinoma.

TTX-030 Plus Budigalimab/mFOLFOX6 Induces Responses in PD-L1–Low Advanced Gastric/GEJ Cancer

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated a statistically significant improvement in progression-free survival (PFS) vs ipilimumab alone as second-line therapy in previously treated patients with stage III unresectable or stage IV melanoma, according to findings from the phase 2 SWOG S1616 trial (NCT03033576) that were presented during the 2022 AACR Annual Meeting.

At a median follow-up of 28.3 months, the median PFS was 3.0 months (90% CI, 2.8-5.3) with the combination vs 2.7 months (90% CI, 2.5-2.9) with ipilimumab alone (HR, 0.63; 90% CI, 0.41-0.97; 

 = .037). The estimated 6-month PFS rates were 34% (90% CI, 25%-44%) and 13% (90% CI, 4%-27%), respectively.

“Subgroups that appear to have done particularly well with the combination therapy include patients with stage IV disease, patients with no prior adjuvant therapy, and patients who received less than 6 months of anti–PD-1 therapy prior to enrollment,” lead study author Ari VanderWalde, MD, MPH, vice president of Clinical Development, Precision Oncology Alliance, Caris Life Sciences, and research faculty at the West Cancer Center & Research Institute, said in the presentation.

The optimal use of immunotherapy is not well defined in melanoma. Available frontline options, such as the combination of ipilimumab and nivolumab, may be too toxic for all patients, and although PD-1 inhibitors have a high response rate, patients will ultimately develop resistance.

As such, the SWOG S1616 trial was designed to understand whether treatment with a CTLA-4 inhibitor alone or in combination with continued PD-1 inhibition can couldreverse primary resistance to PD-1/PD-L1 inhibition in metastatic melanoma.

The study enrolled patients with unresectable stage III or IV melanoma with disease progression on prior PD-1/PD-L1 inhibition. Patients must have achieved a confirmed partial response (PR) or complete response (CR) prior to progression. Patients who progressed on a PD-1/PD-L1 inhibitor in the adjuvant setting were not excluded from enrollment.

Additional eligibility criteria stipulated that patients must have measurable disease per RECIST version v1.1 criteria; a Zubrod performance status of 2 or belowlower; no prior exposure to a CTLA-4 inhibitor;, no history of clinically significant autoimmune disease; and no active central nervous system metastases.

Patients underwent a pretreatment biopsy and were randomized 1:3 to 3 mg/kg of ipilimumab every 3 weeks for 4 doses (n = 24) or the same schedule of ipilimumab plus 1 mg/kg of nivolumab every 3 weeks for 4 doses followed by 480 mg of nivolumab every 4 weeks (n = 70). Additional blood samples and biopsies were taken on days 28 through 35.

Patients underwent tumor assessment every 12 weeks for 1 year. Treatment was continued with clinical benefit, and patients were followed for 2 years.

PFS served as the primary end point of the study. Secondary end points included objective response rate (ORR), overall survival (OS), safety, and the difference in T-cell infiltrate between on-study biopsy samples of responders vs nonresponders.

Between July 2017, and July 2020, 91 eligible patients were treated across 35 sites in the United States.

A total of 23 patients received ipilimumab and 68 received ipilimumab plus nivolumab.

The study arms were well balanced for significant baseline factors. Most patients were male, White, had a performance status of 0, less than 6 months of prior PD-1 therapy, no prior adjuvant therapy, and prior PD-1 therapy only for metastatic disease.

Additional results demonstrated that the ORR was 9% (n = 2; 90% CI, 2%-25%) with ipilimumab alone vs 28% (n = 19; 90% CI, 19%-38%) with the combination (

 = .05). In the ipilimumab arm, there were 0 CRs, 2 PRs (9%), 3 cases of stable disease (13%), and 18 cases of progressive disease (78%). In the combination arm, there were 6 CRs (9%), 13 PRs (18%), 14 cases of stable disease (20%), and 35 cases of progressive disease (51%); 1 patient was not evaluable for response.

The median duration of response was not reached (NR) with ipilimumab vs 18.9 months with the combination. Response was ongoing in 9% of patients on ipilimumab (100% of responders) vs 12% of patients on the combination (42% of responders).

Post-progression therapy for patients from both arms included pembrolizumab (Keytruda; n = 6; 8%), a PD-1 inhibitor (n = 5; 6%), ipilimumab (n = 6; 8%), another immunotherapy (n = 16; 21%), targeted therapy (n = 12; 15%), cytotoxic chemotherapy (n = 4; 5%), and radiation (n = 12; 15%). No significant differences were seen in post-progression therapy between treatment arms; any differences were above the threshold for significance (

At a median follow-up of 27.3 months, the median OS was 21.7 months (90% CI, 15.4-32.4) with the combination vs 25.7 months (90% CI, 8.1-NR) with ipilimumab, failing to reach the threshold for statistical significance (HR, 0.93; 90% CI, 0.54-1.60; 

 = .408). The 12-month OS rates were 63% (90% CI, 52%-72%) and 57% (90% CI, 38%-71%), respectively.

Regarding safety, any-grade adverse effects (AEs) were reported in 87% (n = 20) of patients on ipilimumab vs 93% (n = 63) of patients on the combination. Grade 1 through 3 AEs occurred in 74% (n = 17) of patients in the ipilimumab arm vs 85% (n = 58) of patients in the combination arm. Grade 4 and 5 AEs occurred in 13% (n = 3) of patients vs 7% (n = 5) of patients, respectively.

Grade 3 or greater higher AEs that occurred in at least 5% of patients in the ipilimumab and/or combination arms, respectively, included diarrhea (13% each), aspartate aminotransferase increase (7% each), alanine aminotransferase (7% each), rash (4% vs 6%), fatigue (4% vs 6%), anemia (0% vs 6%), hypotension (0% vs 6%), and hyponatremia (4% vs 6%).

A total of 16% (n = 4) and 23% (n = 16) of patients in the ipilimumab and combination arms, respectively, did not complete all 4 doses of ipilimumab because of an AE.

Correlative analysis demonstrated that the combination led to an increase in CD8+ cells in the tumor and at the boundary in responsive tumors.

“Nivolumab plus ipilimumab is an appropriate next-line treatment in patients without response to anti–PD-1 alone,” VanderWalde concluded.

VanderWalde A, Moon J, Bellasea S, et al. Ipilimumab plus nivolumab versus ipilimumab alone in patients with metastatic or unresectable melanoma that did not respond to anti-PD-1 therapy. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT013.

The combination of nivolumab and ipilimumab demonstrated a statistically significant improvement in progression-free survival vs ipilimumab alone as second-line therapy in previously treated patients with stage III unresectable or stage IV melanoma.

Second-Line Nivolumab Plus Ipilimumab Improves PFS in Advanced Melanoma

Selpercatinib (Retevmo) continued to provide clinically meaningful benefit to patients with metastatic 

 fusion–positive non–small cell lung cancer (NSCLC), according to data from an updated analysis of the phase 1/2 LIBRETTO-001 trial (NCT03157128) presented during the European Lung Cancer 2022 meeting.

The agent elicited a confirmed objective response rate (ORR) of 61.1% (95% CI, 54.7%-67.2%) among 247 patients who previously received platinum chemotherapy. The confirmed ORR achieved with selpercatinib in 69 patients who were treatment naïve was 84.1% (95% CI, 73.3%-91.8%). Moreover, among 26 patients who had measurable central nervous system (CNS) metastases at baseline, selpercatinib produced a CNS-ORR of 84.6%. Notably, 22 of the 26 patients experienced a complete or partial response as their confirmed best response to treatment.

With a median follow-up of 20.3 months in the treatment-naïve population, the median duration of response (DOR) was estimated to be 20.2 months (55.2% censoring rate). At a median follow-up of 21.2 months in the platinum-pretreated population, the median DOR was estimated to be 28.6 months (60.9%).

The estimated median progression-free survival (PFS) in the treatment-naïve and pretreated populations were 22.0 months (53.6% censoring rate; median follow-up of 21.9 months) and 24.9 months (55.9% censoring rate; median follow-up of 24.7 months), respectively. In those with measurable CNS disease, the median intracranial PFS with selpercatinib was 19.4 months. However, the median estimates remain immature.

“The LIBRETTO trial provides the largest set of clinical data for a RET inhibitor and these results continue to demonstrate evidence of meaningful clinical outcomes for patients with metastatic 

 fusion–positive NSCLC treated with [selpercatinib], including those with difficult-to-treat brain metastases,” David Hyman, MD, chief medical officer of oncology at Eli Lilly and Company, stated in a press release.

FDA granted an accelerated approval to selpercatinib

 alteration–positive NSCLC, medullary thyroid cancer, and other thyroid cancers based on earlier data from LIBRETTO-001.

 The regulatory decision is contingent upon data from a confirmatory trial.

The multicenter phase 1/2 LIBRETTO-001 trial enrolled patients with a diagnosis of advanced or metastatic solid tumors harboring 

 Patients needed to have an ECOG performance status ranging from 0 to 2, a QTc of ≤470 msec, and acceptable organ function. Notably, those with asymptomatic CNS metastases were allowed to participate.

A total of 355 patients were eligible for the efficacy analysis; of these patients, 247 patients were previously treated with at least 1 line of platinum chemotherapy and 69 were treatment naïve. Those who received prior treatment had received a median of 2 prior regimens (range, 1-15); 58% of these patients had received anti–PD-1/PD-L1 agents.

The primary end point of the trial was ORR per RECIST v1.1 criteria by independent review, and secondary end points included DOR, PFS, and safety.

The safety findings observed in the cohort proved to be consistent with what is known about selpercatinib. A total of 356 patients who had received at least 1 dose of the agent comprised the safety population. The adverse effects that were experienced by 25% or more of patients included dry mouth, diarrhea, hypertension, increased alanine/aspartate aminotransferase levels, peripheral edema, constipation, rash, headache, and fatigue.

Thirty four percent of patients needed to discontinue treatment with selpercatinib, with 10% doing so because of toxicity. Eleven of these cases were determined to be associated with the study agent.

“We are continuing to build on the robust body of evidence supporting [selpercatinib], including through an ongoing randomized phase 3 confirmatory study, with a planned readout in 2023,” Hyman added.

The phase 3 LIBRETTO-431 (NCT04194944), which is comparing the safety and efficacy of selpercatinib with standard treatment in patients with 

 fusion–positive nonsquamous NSCLC that has spread to other parts of the body, is currently recruiting.

Lilly presents updated data on Retevmo (selpercatinib) in advanced RET fusion-positive non-small-cell lung cancer (NSCLC) at the 2022 European Cancer Congress. News release. Eli Lilly and Company; April 1, 2022. Accessed April 1, 2022. 

FDA approves first therapy for patients with lung and thyroid cancers with a certain genetic mutation or fusion. New release. FDA; May 8, 2020. Accessed April 1, 2022. 

Besse B, Drilon AE, Solomon BJ, et al. Updated overall efficacy and safety of selpercatinib in patients (pts) with 

 fusion+ non-small cell lung cancer (NSCLC). 

. 2021;39(suppl 15):9065. doi:10.1200/JCO.2021.39.15_suppl.9065

A study of selpercatinib (LY3527723) in participants with advanced or metastatic RET fusion-positive non-small cell lung cancer (LIBRETTO-431). ClinicalTrials.gov. Updated March 23, 2022. Accessed April 1, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04194944

Selpercatinib continued to provide clinically meaningful benefit to patients with metastatic RET fusion–positive non–small cell lung cancer.

Pipeline Report: April 2022

Articles

TTX-030 Plus Budigalimab/mFOLFOX6 Induces Responses in PD-L1–Low Advanced Gastric/GEJ Cancer

Second-Line Nivolumab Plus Ipilimumab Improves PFS in Advanced Melanoma