Chris Ryan

Data from a phase 1a trial (NCT04449874) of GDC-6036, a novel KRAS G12C inhibitor, produced encouraging antitumor activity with a manageable safety profile as a single agent in previously treated patients with 

 G12C–mutated non–small cell lung cancer (NSCLC), according to a presentation at the 2022 World Conference on Lung Cancer.

Findings showed that GDC-6036 monotherapy elicited an unconfirmed overall response rate (ORR) of 53% in efficacy-evaluable patients with NSCLC harboring 

 G12C mutations (n = 57) All 30 responders experienced partial responses(PRs). Additionally, the confirmed ORR was 46%, with 26 confirmed PRs.

The oral, highly potent, and selective KRAS G12C inhibitor irreversibly locks the protein in an inactive state to turn off its oncogenic signaling. Preclinical studies showed that GDC-6036 was more potent and selective in vitro compared with sotorasib (Lumakras) and adagrasib (MRTX849).

The phase 1 trial investigated GDC-6036 as a single agent and in combination with various agents in patients with 

 G12C–mutated solid tumors, including NSCLC. During the study, 135 patients with solid tumors received GDC-6036 monotherapy, including 59 with NSCLC.

Eligible patients needed to have locally advanced or metastatic solid tumors, including NSCLC, harboring 

 G12C mutations. Patients needed to have measurable or evaluable disease per RECIST v1.1 criteria, and they were required to have undergone at least 1 prior treatment or be intolerable to standard therapy. Patients with previously treated brain metastases were permitted to enroll, and no prior treatment with a KRAS G12C inhibitor was permitted.

During the dose-escalation portion of the trial, patients with NSCLC received oral GDC-6036 once per day for 21-day cycles at doses of 50 mg (n = 6), 100 mg (n = 5), 200 mg (n = 10), and 400 mg (n = 6). In the dose-expansion portion of the study, 32 additional patients were administered 400 mg of GDC-6036 per day.

The key end points of the trial were safety, pharmacokinetics, and preliminary antitumor activity.

Among all enrolled patients with NSCLC, the median age was 67 years (range, 43-82), 56% were female, and 93% were current or former smokers. The majority of patients had an ECOG performance status of 1 (64%), received prior checkpoint inhibitor therapy (86%), and received prior platinum-based chemotherapy (90%). Of 58 evaluable patients, the median number of prior therapies in the metastatic setting was 1 (range, 0-5). In 45 evaluable patients, 56% were PD-L1 positive.

At the time of data cutoff, 42% of patients discontinued study treatment. Reasons for discontinuation included progressive disease (25%), adverse effects (AEs; 7%), physician decision (5%), clinical progression (3%), and patient withdrawal (2%).

Regarding safety, 88.1% of patients with NSCLC experienced at least 1 treatment-related AE (TRAE) of any grade, including 16.9% who had at least 1 grade 3 or higher TRAE. The most common any-grade TRAEs included nausea (76.3%), diarrhea (61%), vomiting (54.2%), fatigue (23.7%), decreased appetite (15.3%), increased alanine aminotransferase (13.6%), increased aspartate aminotransferase (10.2%), and dyspepsia (6.8%). The most common grade 3 or higher TRAEs included increased alanine aminotransferase (6.8%), increased aspartate aminotransferase (5.1%), diarrhea (3.4%), and fatigue (1.7%).

In all patients treated with single-agent GDC-6036 (n = 135), any-grade TRAEs occurred in 88.1% of patients, and grade 3 or higher TRAEs were reported in 11.1% of patients. Grade 5 events occurred in 7 patients, though all were related to disease progression and were not treatment related.

No dose-limiting toxicities were reported. In patients with NSCLC, AEs leading to GDC-6036 dose modifications, reductions, or withdrawal occurred in 36%, 19%, and 5% of patients, respectively. Those rates were 23%, 10%, and 2%, respectively, in all patients treated with GDC-6036 monotherapy.

Pharmacokinetics evaluated in all patients with solid tumors showed that following a single dose of GDC-6036, ranging from 50 mg to 400 mg, the mean half-life ranged from 13-17 hours. Most patients who received the expansion dose of 400 mg per day were predicted to achieve exposures corresponding to the maximal covalent target engagement from nonclinical studies.

1. Sacher A, Patel MR, Miller Jr. WH, et al. Phase Ia study to evaluate GDC-6036 monotherapy in patients with non­–small cell lung cancer (NSCLC) with 

 G12C mutation. Presented at: 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria; Abstract OA03.04

2. Purkey H. Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers. Presented at: 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract ND11

Articles

A phase 1a trial of GDC-6036 showed encouraging antitumor activity with a manageable safety profile as a single agent in previously treated patients with KRAS G12C–mutated non–small cell lung cancer.

GDC-6036 Monotherapy Reveals Promising Activity in KRAS G12C–Mutant NSCLC

Overall survival (OS) benefit was sustained with second- or third-line tislelizumab (BGB-A317) in patients with non–small cell lung cancer (NSCLC) vs docetaxel in the final analysis of the phase 3 RATIONALE-303 trial (NCT03358875), according to data presented at the 2022 World Conference on Lung Cancer.

Median follow-up for the tislelizumab arm was 16.0 months and 10.7 months for the docetaxel arm. The median OS for patients in the intention-to-treat (ITT) population administered tislelizumab (n = 535) was 16.9 months (95% CI, 15.2-19.1) compared with 11.9 months (95% CI, 9.6-13.5) for patients who received docetaxel (n = 270; HR, 0.66; 95% CI, 0.56-0.79; 

 < .0001). The 12- and 24-month OS rates for tislelizumab were 62.1% and 36.8%, respectively, and 49.7% and 23.7%, respectively, for docetaxel.

Patients with PD-L1 expression of at least 25% of tumor cells (PD-L1 positive) treated with tislelizumab (n = 227) had a median OS of 19.3 months (95% CI, 16.5-22.6) vs 11.5 months (95% CI, 8.2-13.5) with docetaxel (n = 116; HR 0.53; 95% CI, 0.40-0.70; 

 < .0001). The 12- and 24-month OS rates were 67.4% and 42.3%, respectively, for patients in the tislelizumab arm compared with 47.8% and 22.3%, respectively, for patients in the docetaxel arm.

The previously reported interim analysis of RATIONALE-303 showed that tislelizumab significantly prolonged OS vs docetaxel leading to the agent’s approval in China in January 2022 for patients with advanced NSCLC who experienced disease progression after chemotherapy.

RATIONALE-303 enrolled adult patients aged at least 18 years with histologically confirmed, locally advanced, or metastatic squamous or nonsquamous NSCLC. Patients were required to provide fresh or archival tumor tissue samples for PD-L1 evaluation, have an ECOG performance status of 0 or 1, have acceptable hematologic and end-organ function, and have a life expectancy of more than 12 weeks.

Key exclusion criteria included prior treatment with docetaxel or a PD-1, PD-L1, or CTLA-4 inhibitor; the presence of 

 aberrations; a history of severe hypersensitivity reactions to other monoclonal antibodies; or a history of interstitial lung disease.

The trial randomized 805 patients 2:1 to receive 200 mg of intravenous (IV) tislelizumab every 3 weeks or 75 mg/m

OS in the PD-L1–positive and ITT populations served as the trial’s coprimary end points. Secondary end points included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), health-related quality of life, and safety.

Study authors noted that baseline demographics and disease characteristics were representative of the target population, and they were well balanced between both arms, including for PD-L1 expression and histology.

Additional data showed that patients in the ITT population treated with tislelizumab experienced a median PFS of 4.2 months (95% CI, 3.9-5.5) compared with 2.6 months (95% CI, 2.2-3.8) for patients given docetaxel (HR, 0.63; 95% CI, 0.53-0.75). Among PD-L1–positive patients, the median PFS with tislelizumab was 6.5 months (95% CI, 6.2-8.3) vs 2.4 months (95% CI, 2.1-4.1) with docetaxel (HR, 0.37; 95% CI, 0.28-0.49).

The ORR in the ITT population was 22.6% and 7.0% for the tislelizumab and docetaxel arms, respectively. In PD-L1–positive patients, the ORR was 37.4% and 6.9% for tislelizumab and docetaxel, respectively. The median DOR in the ITT population was 13.5 months (95% CI, 8.5-19.6) for tislelizumab compared with 6.0 months (95% CI, 2.1-7.2) for docetaxel. The DOR in the PD-L1–positive population was 11.9 months (95% CI, 8.3-19.6) for tislelizumab and 4.2 months (95% CI, 0.6-6.1) for docetaxel.

A post-hoc biomarker analysis showed that patients with 

 mutations treated with tislelizumab (n = 26) had a median OS of 24.7 months (95% CI, 14.2–not applicable [NA]) compared with 7.7 months (95% CI, 3.3-14.3) in patients with 

 mutations given docetaxel (n = 15; HR, 0.22; 95% CI, 0.10-0.49; 1-sided stratified log-rank 

 = .0002). For patients who did not harbor 

 mutations, the median OS for those treated with tislelizumab (n = 218) was 15.7 months (95% CI, 13.9-17.9) compared with 12.9 months (95% CI, 10.4-14.9) for those administered docetaxel (n = 101; HR, 0.75; 95% CI, 0.57-0.99; 

 mutations who received tislelizumab had a median PFS of 14.1 months (95% CI, 6.2-NA) compared with 2.6 months (95% CI, 2.0-4.1) for those who received docetaxel (HR, 0.17; 0.08-0.37; 

mutations, tislelizumab elicited a median PFS of 4.1 months (95% CI, 2.2-6.2) vs 3.3 months (95% CI, 2.1-4.1) for docetaxel (HR, 0.72; 95% CI, 0.55-0.95; 

Though tumor mutational burden was associated with a PFS benefit for patients treated with tislelizumab vs docetaxel, it was not correlated with an OS benefit, except at the highest cutoff of at least 14 mutations per megabase.

As of the July 25, 2021, data cutoff, 66 patients in the tislelizumab arm and 3 patients in the docetaxel arm were still on treatment. In the tislelizumab group, reasons for discontinuation included radiographic disease progression (n = 229), loss of clinical benefit (n = 121), adverse effects (AEs; n = 61), patient withdrawal (n = 19), clinical progressive disease (n = 23), physician decision (n = 9), concurrent antineoplastic therapy (n = 1), lost to follow-up (n = 2), and other (n = 3).

Reasons for discontinuation in the docetaxel group included radiographic disease progression (n = 168), AEs (n = 32), patient withdrawal (n = 28), clinical progressive disease (n = 15), physician decision (n = 10), concurrent antineoplastic therapy (n = 1), and protocol deviation (n = 1).

No new safety signals were reported in the final analysis. Any-grade treatment-emergent AEs (TEAEs) occurred in 96.8% of patients given tislelizumab compared with 98.4% of patients given docetaxel. The rates of grade 3 or higher TEAEs were 42.1% and 74.8%, respectively.

Common TEAES of any grade included increased ALT (20.6% and 15.1% in the tislelizumab and docetaxel arms, respectively), increased AST (19.5% and 12.4%), decreased weight (16.1% and 11.6%), cough (21.3% and 15.5%), anemia (29.2% and 44.6%), and decreased appetite (16.5% and 24.0%).

1. Zhou C, Huang D, Fan Y, et al. Tislelizumab versus docetaxel in previously treated advanced non-small cell lung cancer: final analysis of RATIONALE-303. Presented at: International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract EP08.01-014.

2. China NMPA approves tislelizumab as second- or third-line treatment for patients with locally advanced or metastatic non-small cell lung cancer. News release. Beigene. January 6, 2022. Accessed August 5, 2022. https://bit.ly/3P7bNJf

3. Comparison of efficacy and safety of anti-PD-1 antibody BGB-A317 versus docetaxel as treatment in second- or third-line setting in participants with NSCLC. ClinicalTrials.gov. Updated June 27, 2022. Accessed August 5, 2022. https://clinicaltrials.gov/ct2/show/NCT03358875

Overall survival benefit was sustained with second- or third-line tislelizumab in patients with non–small cell lung cancer vs docetaxel in the final analysis of the phase 3 RATIONALE-303 trial.

Patients With Previously Treated NSCLC Maintain OS Benefit With Tislelizumab

The combination of toripalimab (Tuoyi) and chemotherapy in the frontline setting shows survival benefit, including improved progression-free survival (PFS), vs chemotherapy alone in patients with advanced non–small cell lung cancer (NSCLC) without 

 mutations, regardless of PD-L1 status, according to a biomarker analysis of the phase 3 CHOICE-01 trial (NCT03856411).

The findings presented at the 2022 ASCO Annual Meeting showed that patients with PD-L1 expressed in at least 50% of tumor cells achieved a median PFS of 10.3 months with toripalimab plus chemotherapy (n = 72) compared with 5.6 months with chemotherapy alone (n = 28; HR, 0.45; 95% CI, 0.27-0.78). The 12-month PFS rates for these patients were 46.4% and 20.3% in the toripalimab and placebo arms, respectively.

In patients with PD-L1 expressed in less than 50% of tumor cells, toripalimab achieved a median PFS of 8.4 months (n = 128) vs 6.7 months for placebo (n = 75; HR, 0.56; 95% CI, 0.40-0.78). The 12-month PFS rates were 39.4% and 20.8% for the toripalimab and placebo groups, respectively.

In patients with PD-L1 expressed in less than 1% of tumor cells, the median PFS for the toripalimab (n = 98) and placebo (n = 41) arms was 8.2 months and 5.6 months, respectively (HR, 0.47; 95% CI, 0.32-0.71). The 12-month PFS rates were 25.9% and 10.3% for the toripalimab and placebo arms, respectively.

For patients with an unknown PD-L1 status, toripalimab elicited a median PFS of 8.4 months (n = 11) compared with 5.5 months for placebo (n = 12; HR, 0.62; 95% CI, 0.21-1.79). The 12-month PFS rates were 37.5% and 11.4%, respectively.

"The addition of toripalimab to chemotherapy in patients with treatment-[naïve] advanced NSCLC provided superior PFS and OS [overall survival vs] chemotherapy alone with a manageable safety profile,” presenting study author Jie Wang, MD, of the State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, said in the presentation.

In March 2022, the final PFS analysis of CHOICE-01 demonstrated that toripalimab plus chemotherapy achieved a meaningful improvement in median PFS in all patients of 8.4 months, compared with 5.6 months for chemotherapy plus placebo (HR, 0.49; 95% CI, 0.39-0.61; 

 < .0001). The interim OS analysis revealed a median OS that was not reached (NR) for toripalimab plus chemotherapy compared with 17.1 months for placebo plus chemotherapy (HR, 0.69; 95% CI, 0.52-0.92; 

CHOICE-01 was a double-blind, placebo-controlled, multicenter trial evaluating toripalimab plus chemotherapy in untreated patients with advanced squamous and nonsquamous stage IIIB and IV NSCLC. Patients were required to be treatment naïve in the locally advanced or metastatic setting, have no known 

 mutations, have measurable disease per RECIST v1.1, have an ECOG performance status of 0 or 1, and have tumor tissue available for PD-L1 testing.

Patients were randomized to receive 240 mg of intravenous toripalimab or placebo on day 1 of every 3-week cycle for up to 2 years. All patients with nonsquamous NSCLC also received pemetrexed plus cisplatin or carboplatin for 4 to 6 cycles, followed by pemetrexed. All patients with squamous NSCLC received nab-paclitaxel plus carboplatin for 4 to 6 cycles.

The primary end point was investigator-assessed PFS per RECIST v1.1, and secondary end points included OS, PFS per blinded independent review committee, overall response rate, disease control rate, time to recurrence, and safety.

Additional data from the biomarker analysis showed patients with a high tumor mutational burden (TMB) experienced an increased survival benefit in the toripalimab arm. For patients with a high TMB, toripalimab induced a median PFS of 13.1 months (n = 77), compared with 5.5 months with placebo (n = 45; HR, 0.34; 95% CI, 0.21-0.54). The 12-month PFS rates were 52.5% in the toripalimab arm and 15.3% in the placebo arm.

The median OS was NR in the TMB-high subgroup median OS for patients assigned to toripalimab compared with 41.1% in the placebo arm (HR, 0.67; 95% CI, 0.38-1.19). The 24-month OS rates were 52.2% and 41.1% in the toripalimab and placebo arms, respectively.

For patients with low TMB, the median PFS was 8.3 months and 6.5 months for the toripalimab (n = 187) and placebo (n = 85) arms, respectively (HR, 0.62; 95% CI, 0.46-0.83). The 12-month PFS rates were 32.8% and 18.5%, respectively.

The median OS was not evaluable (NE) for the toripalimab arm in this subgroup compared with 16.2 months in the placebo arm (HR, 0.68; 95% CI, 0.47-0.98). The 24-month OS rates were 51.3% and 35.0%, respectively.

 mutations saw additional benefits in PFS and OS in the toripalimab arm. Patients harboring those mutations who received toripalimab (n = 83) achieved a median PFS of 9.69 months (95% CI, 8.15-18.53) compared with 8.34 months (95% CI, 6.93-9.69) for patients without 

 mutations (n = 181). The median OS for those patient populations was NE (95% CI, 22.87-NE) and 22.87 months (95% CI, 21.03-NE), respectively.

Patients with IL-7 alterations also achieved additional PFS and OS benefits in the toripalimab arm. Patients with IL-7 alterations who received toripalimab (n = 60) saw a median PFS of 10.87 months (95% CI, 8.08-22.57) compared with 8.34 months (95% CI, 7.16-9.69) in patients without IL-7 alterations (n = 204). The median OS for those groups was NE (95% CI, 12.93-NE) and 22.87 months (95% CI, 21.18-NE), respectively.

Finally, patients with SWI/SNF gene alterations who received toripalimab (n = 45) had a median PFS of 9.92 months (95% CI, 8.08-NE) compared with 8.34 months (95% CI, 7.16-9.69) for patients without those alterations (n = 219). The median OS for those groups was 22.87 months (95% CI, 15.05-NE) and NE (95% CI, 21.88-NE), respectively.

In May 2022, the FDA issued a complete response letter (CRL) regarding the biologics license application for toripalimab plus gemcitabine and cisplatin as first-line treatment for patients with advanced recurrent or metastatic nasopharyngeal carcinoma, as well as for toripalimab monotherapy in the second-line or later treatment of recurrent or metastatic NPC after platinum-containing chemotherapy.

In the letter, the agency asked Coherus Biosciences, Inc and Shanghai Junshi Biosciences Co, Ltd. to alter their quality processes. At the time, the companies planned to meet with the FDA directly and could re-submit this summer.

Wang J. Final progression-free survival, interim overall survival, and biomarker analyses of CHOICE-01: A phase III study of toripalimab versus placebo in combination with first-line chemotherapy for advanced NSCLC without EGFR/ALK mutations. Presented at: 2022 ASCO Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract 362936.

Coherus and Junshi Biosciences receive complete response Letter from US FDA for toripalimab BLA. News release. May 2, 2022. Accessed June 9, 2022. https://bit.ly/3ORWbun

Combination of toripalimab and chemotherapy in the frontline setting shows survival benefit in patients with advanced non–small cell lung cancer without EGFR or ALK mutations, regardless of PD-L1 status.

Improved PFS With Toripalimab Plus Chemotherapy in NSCLC Regardless of PD-L1 Status

When used as a monotherapy, seribantumab, a human anti–HER3 IgG2 monoclonal antibody, demonstrated encouraging overall response rates (ORRs) with acceptable tolerability in patients with solid tumors harboring 

 fusions, according to initial findings from the phase 2 CRESTONE trial (NCT04383210) which were presented at the 2022 American Society for Clinical Oncology Annual Meeting.

In the primary efficacy population of cohort 1 (n = 12), seribantumab induced an ORR of 33%, with a complete response (CR) rate of 17% and a partial response rate of 17%. Additionally, 58% of patients achieved stable disease, and 8% experienced disease progression. In this population, the disease control rate (DCR) with the agent was 92%.

In patients in cohort 1 who specifically had non–small cell lung cancer (NSCLC; n = 11), the ORR achieved with seribantumab was 36%, with 18% of patients achieving a CR and 18% experiencing a PR. Fifty-five percent of these patients had stable disease, and 9% experienced progressive disease. In this group, the DCR with the agent was 91%.

“[These findings are] consistent with prior data [observed] in other studies that [examined] seribantumab in a non–

 fusion population,” lead study author Daniel R. Carrizosa, MD, MS, a medical oncologist and associate professor at the Levine Cancer Institute, of Atrium Health, said in a presentation on the data.

 fusions are rare alterations found in 0.2% of all solid tumors, and 

 fusion proteins bind to and activate HER3. Patients with 

 fusions have been known to experience poor clinical outcomes with standard therapeutic options, including chemotherapy and immunotherapy, and no targeted therapies are currently approved for this population.

Data on preclinical models have shown that seribantumab can inhibit tumor growth and induce tumor regression at clinically achievable concentrations.2 To further explore the agent, investigators launched the global, multicenter, open-label CRESTONE trial.

To be eligible for enrollment, patients had to have locally advanced or metastatic solid tumors harboring 

 fusions per local testing and have received at least 1 prior systemic therapy. Patients could not have tumors harboring any other oncogenic alterations, with the exception of those enrolled to the exploratory cohort 3.

Patients in cohort 1 could not have previously received pan-ERBB–, HER2-, or HER3-targeted therapy. In the exploratory cohort 2, patients needed to have relapsed/refractory disease following pan-ERBB–, HER2-, or HER3-targeted therapy. Lastly, in the exploratory cohort 3, patients were required to have a 

 fusion without an EGF-like domain, or a 

 fusion with other molecular alterations or insufficient tissue for confirmatory testing for 

All patients enrolled to the trial received intravenous seribantumab at 3 g weekly.

The primary end point for those in cohort 1 was ORR by independent central radiologic review and per RECIST v1.1 criteria. Secondary end points included safety, investigator-assessed ORR, duration of response (DOR), progression-free survival, overall survival, and clinical benefit rate.

Patients from cohort 1 were included in the primary efficacy population, and patients from all 3 cohorts were assessed for safety.

In cohort 1, the median age was 61 years (range, 44-76), 67% of patients were female, and 67% were White. Patients had an ECOG performance status of 0 (33%) or 1 (67%). Notably, 14 of 15 patients in cohort 1 had NSCLC, and 1 patient had pancreatic cancer. 

 fusion partners detected in cohort 1 included ATP1B1 (7%), CD74 (40%), SDC4 (13%), SLC3A2 (33%), and other (1%). The median number of prior systemic therapies received was 1 (range, 1-5), and 93% of patients had a confirmed 

 fusion (93%). One patient had an unknown 

Additional efficacy data showed that 92% of patients with tumors harboring 

 fusions experienced tumor reduction from baseline per RECIST v1.1 criteria. The median DOR was not yet reached (range, 1.4-11.5). Moreover, 75% of responses occurred had occurred by the time of the first tumor assessment, which was done at 6 weeks (± 2 weeks). Notably, 75% of responding patients and 53% of all patients remained on treatment at the time of data cutoff.

 fusions, irrespective of fusion partner, the confirmed investigator-assessed ORR achieved with seribantumab was 33% in the overall population (n = 4/12). In those with NSCLC, the ORR per investigator assessment was 36% (n = 4/11). Ninety-two percent of patients experienced tumor reduction from baseline per RECIST v1.1 criteria.

Among all patients evaluable for safety (n = 35), the median age was 65 (range, 19-78), 69% were female, and 66% were White. ECOG performance statuses included 0 (51%) and 1 (49%), and primary tumor types included biliary tract/cholangiocarcinoma (6%), breast cancer (11%), NSCLC (57%), pancreatic cancer (14%), and other (11%). 

 fusion partners among the safety population included ATP1B1 (6%), CD74 (31%), SDC4 (6%), SLC3A2 (17%), AGRN (6%), APP (6%), and other (29%). The median number of prior systemic therapies was 2 (range, 1-6).

Carrizosa also shared a couple of case studies to illustrate the benefit derived with seribantumab. One male who was 70 years of age and who had NSCLC adenocarcinoma previously received 3 lines of therapy, which included platinum-based chemotherapy, immunotherapy, and investigational treatment in the form of immunotherapy plus a targeted agent.

At week 12 of treatment with seribantumab, the patient achieved a PR, with a 35% tumor reduction. At maximum, the patient’s tumor was reduced by 42% with treatment. In this patient, the DOR with the agent was 11.5 months and the response was ongoing. The patient started treatment with the agent under safety run-in and transitioned to receive the agent at a weekly dose of 3 g following induction/consolidation treatment. The patient has been on treatment for 16.0 months.

Another female patient who is 60 years of age and who has NSCLC adenocarcinoma and previously received 3 lines of treatment, including platinum-based chemotherapy and immunotherapy, experienced at PR with seribantumab at week 6 of treatment, with a tumor reduction of 68%. By week 24, investigators noted that the response deepened to a CR. The DOR was 9.7 months in this patient, with a CR that has been ongoing for 5.6 months. The patient has been on treatment for 11.7 months.

Regarding safety, all patients experienced at least 1 treatment-emergent adverse effect (TEAE) with seribantumab, and 49% had at least 1 TEAE that was grade 3 or higher. The most common TEAEs of any grade were diarrhea (49%), fatigue (40%), rash (31%), hypokalemia (29%), nausea (29%), abdominal pain (23%), decrease appetite (23%), hypomagnesemia (23%), cough (20%), anemia (17%), and dysuria (17%). Grade 3 or higher TEAEs included diarrhea (6%), nausea (6%), abdominal pain (6%), hypokalemia (3%), and anemia (3%).

Additionally, 86% of patients experienced at least 1 treatment-related AE (TRAE) of any grade, though only 6% had a TRAE of grade 3 or higher. The most common TRAEs of any grade were diarrhea (40%), fatigue (29%), rash (26%), and nausea (17%).

One dose-limiting toxicity, grade 2 fatigue, was reported, and resulted in a dose reduction during the safety run-in. Seventy-seven percent of patients received the optimized phase 2 dose of 3 g of seribantumab every week. Two patients received dose reductions due to AEs per investigator discretion, including 1 patient who experienced grade 1 alanine aminotransferase increase, and 1 patient who had grade 2 fatigue. Notably, no patients discontinued seribantumab due to AEs.

CRESTONE will continue to investigate seribantumab as a potential new standard of care for patients with solid tumors harboring 

“Importantly, comprehensive genomic profiling with RNA-based sequencing is vital, so we can find patients like these to provide personalized medicine and help them with the treatment of their tumors,” Carrizosa concluded.

1. Carrizosa DR, Burkard ME, Elamin YY, et al. CRESTONE: Initial efficacy and safety of seribantumab in solid tumors harboring NRG1 fusions. 

. 2022;40(suppl 16):3006. doi:10.1200/JCO.2022.40.16_suppl.3006 

2. Odintsov I, Lui AJW, Sisso WJ, et al. The anti-HER3 mAb seribantumab effectively inhibits growth of patient-derived and isogenic cell line and xenograft models with oncogenic NRG1 fusions. 

. 2021;27(11):3154-3166. doi:10.1158/1078-0432.CCR-20-3605

Seribantumab elicited encouraging overall response rates and acceptable tolerability in patients with solid tumors harboring NRG1 fusions.

Encouraging Responses Demonstrated with Seribantumab in Solid Tumors Harboring NRG1 Fusions

Findings from the phase 3 SPOTLIGHT trial (NCT04186845) show that PET/CT scans conducted with 

F-rhPSMA-7.3 result in post-scan upstaging compared with conventional imaging in patients with prostate cancer recurrence, according to updated data presented at the 2022 AUA Annual Meeting.

Among 250 of 366 men in the efficacy analysis population who had negative baseline conventional imaging, 

F-rhPSMA-7.3 showed a correct detection rate between 45% and 47%, which is the percentage of patients scanned with at least one true positive PET finding compared with the Standard of Truth of histopathology or confirmatory conventional imaging. Notably, upstaging results were found to vary based on prior treatment and anatomical region.

F-rhPSMA-7.3 is an investigational prostate‐specific membrane antigen (PSMA)–targeted radiohybrid (rh) PET imaging agent. The agent has a longer half-life, a scope for larger batch productions, and improved spatial resolution in PET images compared with gallium 68.

Prior data from SPOTLIGHT presented at the 2022 Genitourinary Cancers Symposium showed that the overall detection rate in patients who had an evaluable 

F-rhPSMA-7.3 scan was 83% by majority read.

SPOTLIGHT enrolled male patients who were at least 18 years of age and received prior curative intent treatment for localized prostate cancer. Patients were required to have elevated PSA that could indicate biochemical recurrence and be eligible for salvage therapy.

F-rhPSMA-7.3 was administered at a dose of 296 MBq/8 mCi, and PET/CT scans were given between 50 and 70 minutes following injection. Scans were then evaluated by 3 blinded central readers. The Standard of Truth was histopathology or confirmatory conventional imaging. Biopsies took place with 60 days following PET scans, and confirmatory imaging was conducted within 90 days.

Of the 420 patients who consented for the trial, 391 received 

F-rhPSMA-7.3, of which 389 underwent an evaluable PET/CT scan. Furthermore, 366 patients had sufficient data to determine Standard of Truth; these patients comprised the efficacy-evaluable population. Specifically, 69 patients had Standard of Truth determined by histopathology compared with imaging in 297 patients.

In this population, the mean age was 68.4 years (range, 43-85). The median PSA was 1.27 ng/mL (range, 0.03-134.6), and most patients had a Gleason grade group of 3 (30%).

F-rhPSMA-7.3 detection rate was 88% compared with a correct detection rate of 57%.

In patients with negative baseline conventional imaging in the prostate bed region, between 3.5% and 8.0% of patients post prostatectomy showed true positive detections compared with between 39% and 41% of patients post radiation therapy.

In patients with negative baseline conventional imaging in the pelvic lymph node region, between 18% and 21% of patients post prostatectomy showed true positive detections vs 6.5% of patients post radiation. In patients with negative baseline conventional imaging in the extra-pelvic region, between 21% and 26% of patients post prostatectomy showed true positive detections vs between 20% and 30% of patients post radiation.

“It was very interesting for me, as you look closer to the data, that patients who had prostatectomy [were] different than patients who had radiation in the sites of disease,” Fleming said.

Based on the updated data from SPOTLIGHT, 

F-rhPSMA-7.3 could represent a way to better define sites of disease recurrence and identify salvage therapies for the right patients.

“[SPOTLIGHT] showed that we are able to upstage patients [with 

F-rhPSMA-7.3], that we are able to find disease that was missed [by conventional imaging] and gave a false sense of reassurance to patients that they didn’t have recurrence of the disease,” Fleming concluded.

Fleming MT. Impact of 18F-rhPSMA-7.3 PET on upstaging of patients with prostate cancer recurrence: results from the prospective, phase 3, multicenter, SPOTLIGHT study. Presented at: 2022 AUA Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract PLLBA-02.

Blue Earth Diagnostics announces additional results from phase 3 SPOTLIGHT trial of investigational PET imaging agent 18F-rhPSMA-7.3 in biochemical recurrence of prostate cancer. News release. Blue Earth Diagnostics. May 13, 2022. Accessed May 13, 2022. 

Schuster DM. Detection rate of 18F-rhPSMA-7.3 PET in patients with suspected prostate cancer recurrence: results from a phase 3, prospective, multicenter study (SPOTLIGHT). 

. 2022(suppl 6):9. doi:10.1200/JCO.2022.40.6_suppl.009

Use of 18F-rhPSMA-7.3 PET results in post-scan upstaging compared with conventional imaging in patients with prostate cancer recurrence.

18F-rhPSMA-7.3 Increases Upstaging of Disease in Recurrent Prostate Cancer

In patients with primary or secondary central nervous system (CNS) large B-cell lymphoma (LBCL), the chimeric antigen receptor (CAR) T-cell agents, axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (liso-cel; Breyanzi), induced responses without increased risk of cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity syndrome (ICANS).

According to a systematic review and analysis of published data presented at the 2022 Transplantation & Cellular Therapy Meetings, among 113 patients who met the review’s inclusion criteria from 17 prior studies, 56.6% of patients with CNS-involved LBCL achieved a complete response (CR), and 8.9% of patients had a partial response (PR). Additionally, disease progression occurred in 39.8% of patients, and 3.3% of patients had stable disease. Notably, disease progression occurred later in 21.9% and 60% of patients who experienced a CR or PR, respectively.

“We recommend including these patients [with CNS-involved LBCL] in future CAR T[-cell] clinical trials to improve the outcomes of these patients,” study authors Muhammad Husnain, MD, and Noureen Asghar, MD, of the University of Arizona Cancer Center, wrote in the poster presentation.

Axi-cel, tisagenlecleucel, and liso-cel are all FDA-approved for the treatment of patients with LBCL. However, patients with primary and secondary CNS lymphoma have been excluded from clinical trials utilizing these agents because of the risk of toxicities such as CRS and ICANS.

This systematic review aimed to investigate the safety and efficacy of these CAR T-cell therapies in patients with primary/secondary CNS LBCL.

The bibliographic databases MEDLINE, EMBASE, The Cochrane Library, Scopus, and Web of Science were searched to identify all records associated with CAR T-cell therapy published prior to 2021. This included all retrospective and prospective studies reporting the efficacy and safety of CAR T-cell therapy in adult patients with CNS-involved lymphoma. Data on eligible patients from qualified studies were taken, including baseline characteristics, efficacy, and safety.

The systematic review evaluated patient responses as CR, PR, progressive disease, and stable disease. Notably, data on progression-free survival (PFS) was not available for most studies, although it was calculated by combining all patients who were event free and alive in the study, then approximated to the nearest month (1, 3, 6, and 12 months).

Among the patients evaluated, 47.6% were male. Additionally, 28.3% of patients had primary CNS lymphoma, and 71.8% of patients had secondary CNS lymphoma. Most patients received lymphodepleting chemotherapy, fludarabine, and cyclophosphamide prior to CAR T-cell therapy infusion. Notably, 2 patients received a conditioning regimen of BEAM (carmustine, etoposide, cytarabine, and melphalan) plus TBC (thiotepa, busulfan, and cyclophosphamide), and salvage MATRIX chemotherapy (methotrexate and cytarabine plus thiotepa and rituximab [Rituxan]).

All patients were infused with doses of CAR T-cell therapy ranging from 0.6 x 108 T cells to 6 x 108 T cells.

Additional data showed the estimated 1-month response rates were 45.1% for CR, 17.1% for PR, 17.1% for progressive disease, and 12.2% for stable disease.

Notably, 14 studies reported the status of disease for patients at baseline, and 62.8% of patients had active disease at the time of CAR T-cell therapy. Of those patients, 53.5% achieved a CR, 14.1% had a PR, and 36.6% had progressive disease.

The 1-month, 3-month, 6-month, and 12-month PFS rates were 72.1%, 57%, 44.2%, and 37.5%, respectively.

Regarding safety, data from 108 patients across 16 studies were evaluated for CRS, and 70.1% of patients developed grade 1 or 2 CRS, and 6.5% experienced grade 3 or 4 CRS. Additionally, 109 patients from 16 studies were evaluated for ICANS, where data showed 31.8% of patients experienced grade 1 or 2 ICANS, and 21.1% had grade 3 or higher ICANS. Notably, no deaths were reported due to CRS or ICANS.

Data for each CAR T-cell therapy showed that 84.6% of all patients who received axi-cel experienced any-grade CRS, including grade 1 or 2 in 76.9%, and grade 3 or 4 in 10.6%. Furthermore, 69% of patients treated with tisagenlecleucel experienced any-grade CRS, including grade 1 or 2 in 62.1%, and grade 3 or 4 in 6.9%. CRS of any grade occurred in 28.6% of all patients who received liso-cel, and all of those instances were grade 1 or 2.

Regarding ICANS, 70.4% of all patients treated with axi-cel experienced any grade of the toxicity, including 37% who had grade 1 or 2 ICANS, and 34.8% who had grade 3 or 4. ICANS of any grade occurred in 41.4% of all patients who received tisagenlecleucel, including grade 1 or 2 in 34.5%, and grade 3 or 4 in 6.9%. In patients who received liso-cel, 33.3% of patients experienced any grade of ICANS, and all instances were considered grade 3 or 4.

1. Husnain M, Asghar N. Chimeric antigen receptor T cell therapy is effective in primary/secondary CNS large B cell lymphoma: a systematic review and meta-analysis. Presented at: 2022 Transplantation & Cellular Therapy Meetings; Salt Lake City, UT; April 23-26, 2022. Abstract LBA9. 

2. Frigault MJ, Dietrich J, Gallagher KME, et al. Tisagenlecleucel demonstrates safety, efficacy and CNS trafficking in primary CNS lymphoma. 

. 2021;138(suppl 1):258. doi:10.1182/blood-2021-148444

Looking at 4 CAR T-cell agents for the treatment of large B-cell lymphoma, a systematic review and analysis showed that these therapies do not appear to increase the risk of cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome.