Bispecifics Prove to Have Intriguing Role in Lung Cancer

Giorgio V. Scagliotti, MD, PhD

Bispecific antibodies have become an interesting new class of agents in the lung cancer pipeline, most recently with the developments of amivantamab-vmjw (Rybrevant), zenocutuzumab (MCLA-128), and tarlatamab (AMG-757), according to Giorgio V. Scagliotti, MD, PhD, in a presentation during the 22nd Annual International Lung Cancer Congress, a program hosted by the Physicians’ Education Resource®, LLC.¹

“In thoracic malignancies, we have [these important] studies [highlighting these agents],” said Scagliotti, chief of the Medical Oncology Division, Department of Oncology at the University of Torino, in Italy. “[There is the role of amivantamab] in exon 20 insertion mutations, MCLA-128 in NRG1 fusion–positive tumors, and AMG 757 in small cell lung cancer.”

Bispecific antibodies across human diseases hold great therapeutic promise through their ability to bridge cells on either effector cells or target cells, or on tumor cells through receptor inhibition. However, Scagliotti emphasized that translating the concept of bispecifics into practical treatments has been a challenge. In 2009, the first bispecific antibody catumaxomab was approved in the European Union as an intraperitoneal therapy of malignant ascites, but was found to be toxic for Fc-mediated off-target T-cell activation in the liver and was voluntarily withdrawn from market.

Emicuzumab (Hemlibra) is indicated for the treatment of patients with hemophilia A. In oncology, blinatumomab (Blincyto), a bispecific CD19-directed CD3 T-cell engager, is approved for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease greater than or equal to 0.1%, as well as those with relapsed/refractory B-cell precursor ALL.

“There was a lot of interest around the chronic inflammatory disorders, and only [recently there has been] a growing interest in the field of malignancies,” Scagliotti said.

Amivantamab

The fully human EGFR-MET bispecific antibody amivantamab has immune-cell-directing activity that targets activating and resistance EGFR mutations, as well as MET mutations and amplifications.

The agent has been evaluated in the phase 1 CHRYSALIS study (NCT02609776), where investigators enrolled patients with advanced non–small cell lung cancer (NSCLC) on a dose-escalation cohort from 140 mg to 1750 of amivantamab in an effort to determine the recommended phase 2 dose (RP2D).² This was determined to be 1060 mg for those with a weight lower than 80 kg, or 1400 mg for those 80 kg or higher.

Cohort D of the single-arm trial was comprised of patients with EGFR exon 20 insertion mutations who progressed on platinum-based chemotherapy. The safety population (n = 114) included this subset treated at the RP2D; the efficacy population (n = 81) featured those who had at least 3 disease assessments at clinical cutoff. By October 8, 2020, all responders in the efficacy population had at least 6 months of follow-up from their first disease assessment.

The primary end point was overall response rate (ORR) via RECIST v1.1 criteria; key secondary end points were clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

The median age of the efficacy population was 62 years (range, 42-84), and 59% of patients were female. Nearly half (49%) were Asian, followed by White (37%), Black (3%), and not reported/multiple (11%). Fifty-three percent of patients were nonsmokers, and the median time from initial diagnosis was 17 months (range, 1-130). A total 22% of patients had a history of brain metastases, the median number of prior lines of therapy was 2 (range, 1-7), and prior systemic treatments (100%) included platinum-based doublet chemotherapy (100%), immunotherapy (46%), poziotinib (1%), or an EGFR TKI (25%) that was of first (9%), second (7%), or third generation (7%).

Through blinded independent central review (BICR) assessment and at a median follow-up of 9.7 months (range, 1.1-29.3), the ORR was 40% (95% CI, 29%-51%), which included 3 complete responses (CRs) and 29 partial responses (PRs); the stable disease (SD), progressive disease, and not evaluable rates were 48%, 10%, and 1%, respectively. The median duration of response (DOR) was 11.1 months (95% CI, 6.9–not reached [NR]) and the CBR was 74% (95% CI, 63%-83%).

Additionally, the best ORR and CBR by insertion region of exon 20, as detected by circulating tumor DNA (ctDNA; n = 80), was 100% and 100% in the helical region (n = 1); 41% and 70%, respectively, in the near loop (n = 54); 25% and 75% in the far loop (n = 8), and 39% and 83% in not detected by ctDNA (n = 18). Twenty-five distinct exon 20 insertion variants were identified through next-generation sequencing of ctDNA with Guardant360 from 63 evaluable patient samples.

“More relevantly, at the clinical level—at least for me—there is a significant proportion in the spider plot that is showing that […] you can obtain significant tumor shrinkage, but you can also have long-lasting responses,” Scagliotti pointed out.

At the time of data cutoff, 47% of patients remain on treatment, and 63% had responses lasting 6 months or longer. The median PFS and OS was 8.3 months (95% CI, 6.5-10.9) and 22.8 months (95% CI, 14.6–NR), respectively.

The safety profile of amivantamab was consistent with that of EGFR and MET inhibition, Scagliotti explained. In the safety population (n = 114), 2% of patients discontinued due to rash, and 12% had diarrhea (grade 1/2, 8.5%; grade 3, 3.5%)—10% of which was related to treatment. A total 94% of infusion-related reactions (IRRs) occurred with the first infusion, but this did not significantly impact patients’ ability to continue on subsequent treatments.

Based on these data, the FDA approved amivantamab in May 2021 as the first treatment for adult patients with NSCLC who harbor EGFR exon 20 insertion mutations.³ The regulatory agency also granted an approval to Guardant360 CDx for use as a companion diagnostic for the bispecific antibody.

Zenocutuzumab

NRG1 fusions are observed at low incidence across tumors that preserve the EGF-like domain and are potentially actionable; they are best detected through RNA-NFS. HER2-directed therapy has been found to be a suboptimal strategy but are currently under investigation.

Zenocutuzumab is being tested in the phase 1/2 eNRGy trial (NCT02912949), which is enrolling patients with NRG1 fusion–positive solid tumors. Investigators presented pooled data from eNRGy at the 2021 ASCO Annual Meeting.⁴ The dataset comprised patients with pancreatic ductal adenocarcinoma (PDAC; n = 12), NSCLC (n = 25), and other malignancies (n = 10).

In the NSCLC cohort, the median age was 58 years (range, 32-84), 60% of patients were female, and 40% of patients had an ECOG performance status of 0. Twenty-one (84%) patients had adenocarcinoma histology, followed by 3 (12%) with invasive mucinous adenocarcinoma, and 1 (4%) with other histology.

In 24 evaluable patients with NSCLC, the confirmed ORR was 25%; 1 additional PR was confirmed after the cutoff date, bringing the ORR in this subset to 29% (7/24).

The bispecific antibody also showed promise in other solid tumors. The ORRs for the 12 patients with PDAC and 9 patients with other NRG1 fusion–positive cancers were 42% and 22%, respectively. Additionally, tumor reduction was reported for 34 patients (76%) overall.

Regarding safety, the majority of adverse events (AEs) with zenocutuzumab were grade 1/2, with a notable absence of severe gastrointestinal toxicity, skin toxicities, and clinical cardiotoxicities. All-grade and grade 3/4 treatment-related AEs (TRAEs) occurred in 59% and 3% of patients, respectively, including diarrhea (all-grade, 20%; grade 3/4, 0%), asthenia/fatigue (all-grade, 13%; grade 3/4 <1%), nausea (all-grade, 10%; grade 3/4, 0%), and infusion-related reaction (all-grade, 7%; grade 3/4, 1%). No grade 4 treatment-related AEs were reported, with 1 grade 5 AE hypersensitivity occurring in 1 patient with preexisting severe aortic stenosis that was previously reported.

Tarlatamab (AMG 757)

Tarlatamab, a half-life extended bispecific T-cell engager against DLL3, is being explored in small cell lung cancer (SCLC). Updated results from a multicenter, open-label, phase 1 trial (NCT03319940) with the novel agent in this patient population were also presented at the 2021 ASCO Annual Meeting.⁵

Patients with SCLC had to have received at least 1 line of systemic therapy and either progressed or recurred following at least 1 platinum-based chemotherapy, as well as an ECOG performance status of 0 to 2, at least 1 measurable lesion, and adequate organ function.

In the study of 66 patients, the median age was 64 years (range, 32-80), 74% of patients were former smokers, and 98% of patients had an ECOG performance status of 0 to 1. Patients had either 1 to 2 (73%) or more than 3 (27%) prior lines of therapy; the median number of prior treatments was 2 (range, 1-6). Forty-four percent of patients had received prior anti–PD-1/PD-L1 therapy. Most patients (95%) had extensive-stage disease at initial diagnosis; 24% had brain metastases and 47% had liver metastases.

Data showed that tumor shrinkage was observed across tarlatamab doses, which ranged from 0.3-mg to 100-mg target doses. At a median follow-up of 11.2 months, the confirmed PR rate of 64 evaluable patients was 20%; the unconfirmed PR rate was 2%. The SD and disease control rates were 27% and 47%, respectively. For patients with a confirmed PR (n = 13), the median DOR was 8.7 months, the median time to response was 1.8 months.

Fifteen percent of patients completed at least 6 months of treatment, and 7 of 13 patients with confirmed PR are still on treatment and have an ongoing response.

Five percent of patients discontinued treatment due to TRAEs; dose-limiting toxicities included grade 5 pneumonitis at the 0.3-mg dose in 1 patient and grade 3 encephalopathy at the 100-mg dose in 1 patient.

Grade 3 or higher TRAEs occurred in 27% of patients. Additionally, 44% of patients experienced all-grade cytokine release syndrome; 1 patient had this as a grade 3 or higher TRAE.

“The main problem is related to cytokine release syndrome that is manageable and reversible in the vast majority of the cases, but we need to keep an eye on it,” Scagliotti added.

Select bispecific antibody constructs are currently being investigated in other solid malignancies, including the HER2-targeted ISB 1302 in breast cancer (NCT03983395), the PD-1/CTLA-4–directed AK104 in gastric cancer/gastroesophageal junction adenocarcinoma (NCT03852251), the EGFR-directed variant III AMG 596 in glioblastoma (NCT03296696), the PSMA-targeted AMG 160 in metastatic castration-resistant prostate cancer (mCRPC; NCT03792841) and pasotuxizumab (NCT01723475), the GD2-directed GD2Bi-aATC in OS/NB (NCT02173093), the MUC16-directed REGN4018 in ovarian cancer (NCT03564340), and the GD2-targeted Hu3F8-BsAb GD2 in solid tumors (NCT03860207).

References

1. Scagliotti, GV. Bispecific antibodies in lung cancer. Presented at: the 22nd Annual International Lung Cancer Congress; July 30-August 1, 2021; Huntington Beach, CA.
2. RYBREVANT - CHRYSALIS Study. JanssenMD. Updated June 17, 2021. Accessed July 30, 2021. https://bit.ly/3rL83Dy
3. FDA approves first targeted therapy for subset of non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed May 21, 2021. https://prn.to/3hOrU1t
4. Schram AM, O’Reilly EM, O’Kane GM, et al. Efficacy and safety of zenocutuzumab in advanced pancreas cancer and other solid tumors harboring NRG1 fusions. J Clin Oncol. 2021;39(suppl 15):3003. doi:10.1200/JCO.2021.39.15_suppl.3003
5. Owonikoko TK, Champiat S, Johnson ML, et al. Updated results from a phase 1 study of AMG 757, a half-life extended bispecific T-cell engager (BiTE) immuno-oncology therapy against delta-like ligand 3 (DLL3), in small cell lung cancer (SCLC). J Clin Oncol. 2021;39(suppl; abstr 8510). doi:10.1200/JCO.2021.39.15_suppl.8510