June 2020 Edition Vol.11, Issue 6

Promising Personalized Therapies at ASCO 2020

By Lynne Lederman, PhD

Several presentations at this year’s ASCO virtual scientific program focused on therapies that should expand opportunities for personalized treatment of patient populations with unmet needs. Three studies in new indications for the antibody-drug conjugate (ADC) Enhertu (trastuzumab deruxtecan) may expand the use of this agent. There was also encouraging data for cell-based therapies for two as-yet incurable hematologic malignancies.

Trastuzumab deruxtecan (T-DXd; DS-8201) in HER2-altered tumors

T-DXd is an ADC with a cleavable tetrapeptide-based linker combining a HER2-specific monoclonal antibody with a cytotoxic topoisomerase I inhibitor “payload” having the same mechanism of action as irinotecan. The drug:antibody ratio is high at 8:1. The cleaved payload is membrane permeable, which may allow diffusion out of HER2-positive cells to neighboring negative cells for bystander killing. T-DXd (fam-trastuzumab deruxtecan-nxki in the US) was recently approved for the treatment of HER2 positive, previously treated, unresectable or metastatic breast cancer.

Colorectal cancer

DESTINY-CRC01 is a phase 2, multicenter, open-label study (NCT03384940) of T-DXd in patients with HER2-expressing, RAS and BRAF wild type (wt), metastatic colorectal cancer (CRC) after failure of ≥2 prior lines of standard therapies including anti-HER2 therapies. History of or suspected interstitial lung disease (ILD) was an exclusion factor because it is a known serious adverse event (AE) with T-DXd (Abstract 4000).

T-DXd was administered IV at 6.4 mg/kg every 3 weeks, a dose that is higher than the 5.4 mg/kg approved dose for breast cancer. Patients were divided into 3 cohorts by HER2-positivity using immunohistochemistry (IHC) or in situ hybridization (ISH): cohort A (n=53; IHC 3+ or IHC2+/ISH+), cohort B (n=7; IHC2+/ISH-), and cohort C (n=18; IHC 1+). The primary endpoint was overall response rate (ORR) confirmed by independent central review (ICR) in cohort A.

Patients had a median of 4 prior lines of therapy; 75% of patients in cohort A were IHC 3+, 25% were IHC2+/ISH+. ORR in cohort A was 45.3% (95 CI, 31.6%-59.6%) with 1 complete (CR) and 23 partial responses (PR); there were no confirmed responses in cohort B or C. Duration of response (DOR) was not reached. Median progression-free survival (PFS) was 6.9 months in cohort A; overall survival (OS) was not reached in any cohort. In a subgroup analysis, only HER2 status 3+ versus 2+/ISH+ was associated with responses.

Treatment-related AE were as expected, and most were grade 1/2. There were 2 drug-related deaths (1 ILD, 1 pneumonitis). Grade 3/4 AE included cytopenias and gastrointestinal AE. ILD occurred in 5 patients of whom 2 recovered. Presenter Salvatore Siena, MD, Niguarda Cancer Center, Milan, Italy, said ILD is an important risk, requiring careful monitoring and intervention, including steroids and T-DXd discontinuation.

Discussant Michael S. Lee, MD, University of North Carolina at Chapel Hill, emphasized that anti-HER2 targeted therapy is only effective in patients with RAS wt disease; HER2 amplification occurs in only 5% to 12% of RAS wt CRC, and RAS mutations are not mutually exclusive with HER2 amplification. He noted that although T-DXd showed activity in HER2 low expressing breast cancers, this does not seem to be the case for CRC. In HER2+ CRC, he found the response rates impressive, and were comparable in patients who received prior irinotecan (n=16) to that of the HER2-positive cohort. He concluded, “I would consider this to be the best data so far for subsequent anti-HER2 therapy in metastatic CRC.”

In a highlights broadcast session, discussant Autumn McRee, MD, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, said, “without a doubt, this trial is clinically relevant. Is it practice-changing? Maybe. I think it’s still to be determined how to sequence HER2 targeted therapies.” Testing for HER2 amplification in CRC should be considered standard of care, although a standard definition of HER-2 positivity is needed.

Gastric cancer

Results of the open-label, randomized, phase 2 DESTINY-Gastric01 trial (NCT03329690), which evaluated T-DXd in patients with HER2-positive, unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma were presented in a poster and published in conjunction with the meeting.1 HER2-amplification or overexpression occurs in 15% to 20% of advanced gastric/GEJ tumors. Prior studies showed no survival benefit with anti-HER2-targeting agents in these cancers (Abstract 4513).

In this study, patients were randomly assigned 2:1 to T-DXd (IV at 6.4 mg/kg every 3 weeks; n=125) or to treating physician’s choice (PC) of irinotecan (n=55) or paclitaxel (n=7). The primary endpoint was ORR; secondary endpoints included OS, duration of response, PFS, ICR confirmed ORR, and safety. Patients received a median of 2 prior therapies, including trastuzumab or a trastuzumab biosimilar. Patients were Asian (about 80% Japanese, about 20% from South Korea).

ORR was 51.3% for T-DXd versus 14.3% for PC (P<.0001). Confirmed ORR was 42.9% for T-DXd versus 12.5% for PC. Median duration of confirmed response was 11.3 months for T-DXd versus 3.9 months for PC. OS was 12.5 months for T-DXd versus 8.4 months for PC (HR, 0.59; 95% CI 0.39-0.88; P=.0097). Median PFS was 5.6 months for T-DXd versus 3.5 months for PC (HR, 0.47; 95% CI 0.31-0.71).

There was 1 T-DXd-related death from pneumonia; 9.6% of patients (n=12) had drug-related ILD or pneumonitis, most of which were mild and resolved. There were no new safety signals, with mostly GI or hematologic AE.

Presenter Kohei Shitara, MD, National Cancer Center Hospital East, Chiba, Japan, suggested T-DXd may be an effective option for HER2-positive gastric/GEJ adenocarcinoma that has progressed after trastuzumab. He and coauthors acknowledge that study limitations include lack of ethnic diversity and a small sample size.1

Discussant Mohamedtaki Abdulaziz Tejani, MD, AventHealth Cancer Institute, Orlando, Florida, called T-DXd an effective treatment option in the second-line setting. He pointed out that gastric/GEJ cancer is genotypically different in Asian versus Western populations, and that difference extends to response to treatment. Whether Western patients will benefit as much remains to be seen. With such a durable benefit this drug should be looked at in the first-line setting and compared with trastuzumab, he suggested.

View an OBR interview with Dr. Howard Hochster on Enhertu data from a phase 2 gastric cancer trial of Asian patients:

Non-small cell lung cancer (NSCLC)

Egbert F. Smit, MD, Netherlands Cancer Institute, Amsterdam, Netherlands, presented interim results of DESTINY-Lung01 (NCT03505710), a phase 2, open-label, multicenter study of T-DXd in patients with unresectable or metastatic, relapsed or refractory non-squamous NSCLC with a HER2 expressing (ICH 3+ or 2+; n=42) or activating (n=42) mutation. Prior pan-HER tyrosine kinase therapy and no other HER2-targeted therapy was allowed. The primary endpoint was confirmed ORR by ICR (Abstract 9504).

Results for patients in the HER2 mutated cohort at a median 9.0 months of follow-up were presented. ORR was 61.9% with 1 CR and 25 PR. Median PFS was 14.0 months; median OS and duration of response were not reached. The AE profile was similar to that of the other T-DXd studies. None of the 5 deaths were treatment-related. Five patients experienced low-grade ILD.

Discussant Grace K. Dy, MD, Roswell Park Comprehensive Cancer Center, Buffalo, New York, pointed out that because low levels of HER2 are expressed in the lung, ILD is an on-target toxicity. “More investigation into the mechanism and risk factors for ILD will be crucial, especially in light of ongoing and planned combination trials with immune checkpoint inhibitors and other tyrosine kinase inhibitors,” she said (Figure 1).


Newer CAR strategies in hematologic malignancies

Non-Hodgkin lymphoma (NHL)

Aravind Ramakrishnan, MD, Sarah Cannon Research Institute, Austin, Texas, presented updated results of safety and preliminary efficacy of the Alexander phase 1/2 study (NCT03287817) of AUTO3, the first bicistronic chimeric antigen receptor (CAR) targeting both CD19 and CD22, followed by pembrolizumab in relapsed/refractory diffuse large B cell lymphoma (rrDLBCL) (Abstract 8001).

This study tests whether dual targeting of CD19 and CD22 simultaneously will reduce antigen escape and improve duration of CR. CAR-T cells may upregulate PD1 upon stimulation, so the study is testing whether the addition of pembrolizumab to the pre-conditioning regimen will prevent CAR-T cell exhaustion.

Alexander is a single-arm, open-label, multi-center phase 1/2 study. Dose escalation started with 50 million CAR-T cells and preconditioning with fludarabine and Cytoxan. Initial cohorts did not include pembrolizumab. Later cohorts introduced pembrolizumab with 3 doses to test safety at day 14. After low rates of cytokine release syndrome (CRS) and neurotoxicity, pembrolizumab was initiated on day minus 1 to reduce early CAR-T exhaustion and engage baseline PD-L1-positive tumors. Dose escalation completed at 450 million CAR-T cells, with the recommended phase 2 efficacy cohort dose at 150 to 450 million.

The primary objective of phase 1 was the incidence of grade 3 or higher AE occurring within 75 days of AUTO3 infusion, and the frequency of dose-limiting toxicities (DLT). The 23 patients enrolled had high-risk disease.

The majority of treatment emergent AE of all grades and grade 3 or higher were hematologic, as expected. There were no DLT and no AUTO3-related deaths. There were 6 grade 1 and 3 grade 2 CRS, and no grade 3 or higher CRS. No prophylaxis was needed; 17% of patients received atezolizumab. There was 1 case of late, atypical grade 3 neurotoxicity in a patient receiving 50 million cells without pembrolizumab that resolved with steroids. No other patients have experienced neurotoxicity with higher doses and pembrolizumab.

Dr. Ramakrishnan said that the safety profile appears better for CRS and neurotoxicity than the currently approved CD19 CAR-T cell products. Low grade CRS may be the result of levels of cytokines in patients receiving AUTO 3 that are lower than those reported for patients receiving axicabtagene ciloleucel.

CR has been seen in all doses tested with an ORR of 65% and CR rate of 48%. At doses greater than 150 million cells, ORR was 69% and CR was 56%. CR was 63% for those receiving 150 million cells and pembrolizumab on day minus 1. Of note, manufacturing has been successful in all patients. At the short follow-up of 3 months, 10 of 11 CR were ongoing. An outpatient expansion cohort is expected to enroll soon.

Multiple myeloma (MM)

Jesus G. Berdeja, MD, Sarah Cannon Research Institute, Nashville, Tennessee, presented updated results of CARTITUDE-1, a phase 1b/2 study (NCT03548207) of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T cell therapy in progressive rrMM. JNJ-4528 a signaling domain, a costimulatory domain, and 2 BCMA-targeting single chain antibody binding domains to confer avidity (Abstract 8505).

The primary objective of phase 1b is safety and confirmation of the phase 2 dose as suggested by the prior LEGEND-2 study, and of phase 2 is efficacy. Target dose was 0.72 x 106 CAR-positive viable T cells per kilogram. Of 35 patients enrolled and apheresed, 30 underwent lymphodepletion and 29 were dosed. Of these, the median age was 60 years; 10% had extramedullary plasmacytoma, and 27% had high-risk cytogenetic profiles.

CRS occurred in 93%, mostly grade 1 or 2, with 2 grade 3. Neurotoxicity consistent with immune effector cell‐associated neurotoxicity syndrome (ICANS) occurred in 10%, with 1 grade 3 or higher. Other AE were primarily hematologic, with 100% grade 3 or 4 neutropenia, and most experiencing thrombocytopenia and anemia. Non-hematologic AE were less frequent and mostly grade 1 or 2.

The ORR was 100% with stringent CR of 86%, and at least very good partial response of 97%. ORR was independent of BCMA expression on myeloma cells at baseline. At a median follow-up of 11.5 months, 22 of 29 patients are alive and progression free. PFS at 9 months was 86%. Most patients had negative minimal residual disease beyond day 28. Dr. Berdeja concluded by mentioned that JNJ-4528 has received a breakthrough therapy designation. Phase 2 of the study is completely enrolled and phase 2 and 3 studies have been initiated.

Discussant Krina Patel, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, thought the efficacy in this study was fantastic and an impressive start given it is an early trial. Questions to be answered include determining the mechanisms of resistance to improve CAR-T products and figuring out the best sequencing and combinations of therapies. Moving CAR-Ts to the outpatient setting will be important, as will improving patient access to trials and CAR-T therapies.

View an OBR interview with Dr. Saad Usmani on the updated data on CARTITUDE-1 at ASCO20:


References:

  1. Shitara K, Bang Y-J, Iwasa S, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. May 29, 2020; DOI: 10.1056/NEJMoa2004413.
  2. https://clinicaltrials.gov/ct2/show/NCT03334617
  3. https://clinicaltrials.gov/ct2/show/NCT04014075
  4. https://clinicaltrials.gov/ct2/show/NCT03505710
  5. https://clinicaltrials.gov/ct2/show/NCT04042701
  6. https://clinicaltrials.gov/ct2/show/NCT03523572
  7. https://clinicaltrials.gov/ct2/show/NCT03523585
  8. https://www.clinicaltrials.gov/ct2/show/NCT03529110
  9. https://www.clinicaltrials.gov/ct2/show/NCT03529110

 

Post a Comment

OBR Archives

To view previous issues of OBR green you can visit our archives. The entire library of OBR green articles is searchable.