Clinical Catch-Up: September 21-25
The European Society of Medical Oncology (ESMO) Virtual Congress 2020 was last weekend and the beginning of the week, which resulted in numerous clinical trial announcements. Here’s a look.
COVID-19-Related
Johnson & Johnson announced it is launching its large-scale, international Phase III trial for its vaccine candidate, JNJ-78436735. The vaccine was developed by J&J’s Janssen Pharmaceutical Companies using its AdVac technology platform, which was also used to develop Janssen’s Ebola vaccine that was approved in Europe and to develop its Zika, RSV, and HIV vaccine candidates. J&J’s Phase III ENSEMBLE trial will evaluate the safety and efficacy of a single dose compared to placebo in up to 60,000 adults ages 18 years and older, with “significant representation from those that are over age 60.” It expects to enroll volunteers in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa and the U.S.
Global Response Aid (GRA) and Dr. Reddy's Laboratories announced the antiviral Avigan demonstrated promising results in a Phase III trial in Japan in COVID-19. Patients who received the drug recovered from symptoms 2.8 days earlier, on average, compared to the control group. The trial was sponsored by FujiFilm Toyama Chemical. Avigan contains the active ingredient Favipiravir and was originally developed as an anti-influenza drug.
ARCA biopharma submitted an IND to the FDA to evaluate AB201 for treatment of patients hospitalized with COVID-19. They hope to initiate the Phase IIb part of a sequential Phase IIb/III trial as early as the fourth quarter of this year. AB201 is a small recombinant protein being developed as a potential treatment for RNA virus-associated disease. It is a potent, selective inhibitor of tissue factor (TF).
Non-COVID-19-Related
AstraZeneca and Merck announced final results from the Phase III PROfound trial demonstrating Lynparza showed a statistically significant and clinically meaningful improvement in overall survival (OS) compared to enzalutamide or abiraterone in metastatic castration-resistant prostate cancer (mCRPC) who have BRCA1/2 or ATM gene mutations. Patients had progressed on previous treatment with enzalutamide and/or abiraterone.
AstraZeneca also updated results from the PACIFIC Phase III trial of Imfinzi in unresectable NSCLC who had not progressed on concurrent chemoradiation therapy (CRT). The post-hoc analyses showed an estimated four-year OS rate of 49.6% for Imfinzi compared to 36.3% for placebo after CERT. Median OS was 47.5 months for Imfinzi compared to 29.1 for placebo.
Merck presented new data for three investigation drugs: data from cohort expansions of a Phase Ib trial of vibostolimab as a monotherapy and in combination with its checkpoint inhibitor Keytruda in metastatic non-small cell lung cancer; first-time Phase I data for MK-4830 in advanced solid tumors demonstrating acceptable safety profile and early signals of anti-tumor activity; late-breaking Phase II data for MK-6482 demonstrated anti-tumor responses in von Hippel-Lindau (VHL) disease patients with clear cell renal cell carcinoma (RCC) and other tumors. Fibostolimab is an anti-TIGIT therapy. MK-4830 is an antibody against immunoglobulin-like transcript 4 (ILT4). MK-6482 is an oral HIF-2alpha inhibitor.
Janssen Pharmaceutical of Johnson & Johnson announced interim results from the CHRYSTALIS trial of amivantamab in combination with the third-generation EGFR tyrosine kinase inhibitor (TKI) Lazertinib in non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or L858R mutations. Amivantamab is a fully human bispecific antibody that targets epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition factor (MET) mutations.
Merck and Eisai presented new data from two trials under the LEAP clinical program evaluating Keytruda plus Eisai’s Lenvima in unresectable or advanced melanoma that had previously progressed on an anti-PD-1/PD-L1 therapy. Lenvima is an orally available multiple receptor TKI. In the Phase II LEAP-005 trial, the combination demonstrated an ORR of 9.7%-32.3% in previously treated patients with triple-negative breast cancer, ovarian cancer, gastric cancer, and colorectal cancer. In the LEAP-004 Phase II trial of Keytruda and Lenvima in unresectable or advanced melanoma that had progressed on an anti-PD-1/PD-L1 therapy within 12 weeks, at a June 10 data cutoff, the combination demonstrated an overall ORR by blinded independent central review (BICR) of 21.4% with a CRR of 1.9% and a partial response rate of 19.4%.
MD Anderson Cancer Center and Amgen reported Phase I trial results for patients with advanced solid tumors marked by KRAS G12C mutations treated with sotorasib (AMG 510). With patients with KRAS G12C-mutant advanced NSCLC, the therapy demonstrated a confirmed response rate of 32.2% and disease control rate of 88.1% across all dose levels. In patients with KRAS G12C-mutant colorectal cancer, response rate was 7.1% and disease control rate was 73.8%.
Merck and the European Organization for Research and Treatment of Cancer (EORTC) announced new and updated findings from the Phase III EORTC1325/KEYNOTE-054 trial of Keytruda as adjuvant therapy in resected, high-risk stage III melanoma. The data showed that with 3.5 years of follow-up, Keytruda hit the key secondary endpoint of distant metastasis-free survival (DMFS), decreasing the risk of distant metastasis or death by 40% compared to placebo, with 3.5-year DMFS rates of 65.3% and 49.4%, respectively.
Merck also presented five-year survival results from the Phase III KEYNOTE-024 trial, which demonstrated a sustained, long-term survival benefit and durable responses with Keytruda compared to chemotherapy as first-line treatment in metastatic NSCLC whose tumors express PD-L1 with no EGFR or ALK genomic tumor aberrations. At five years, OS rate was twice as high for patients who received Keytruda versus chemotherapy. Keytruda also reduced risk of death by 38% compared to chemotherapy.
Merck also announced first-time data from the Phase III KEYNOTE-590 trial of Keytruda in combination with platinum-based chemotherapy for the first-line treatment of locally advanced or metastatic esophageal and gastroesophageal junction (GEJ) cancer. The combination significantly improved OS, decreasing risk of death by 27%.
Morphic Therapeutic dosed the first healthy volunteers in its Phase I program for MORF-057, which is being developed for inflammatory bowel disease (IBD) with an initial focus on ulcerative colitis (UC). MORF-057 is a selective, oral small molecule inhibitor of the alpha4beta7 integrin.
Immunomedics announced data from the confirmatory Phase III ASCENT trial demonstrated that Trodelvy (sacituzumab govitecan-hziy) significantly extended OS and improved ORR and clinical benefit rate (CBR) compared to treatment of choice (TPC) standard single-agent chemotherapy in brain metastases-negative patients with mTNBC who had previously received at least two previous therapies for metastatic disease. Trodelvy is an antibody-drug conjugate (ADC) directed against Trop-2.
Bristol Myers Squibb and Exelixis presented the first data from the pivotal Phase III CheckMate -9ER trial of Opdivo (nivolumab) in combination with Cabometyx (cabozantinib) that demonstrated significant improvements across all efficacy endpoints, including OS in previously untreated advanced renal cell carcinoma (RCC). The combination reduced the risk of death by 40% compared to sunitinib.
Regeneron Pharmaceuticals and Sanofi presented positive results from the pivotal Phase II trial of PD-1 inhibitor Libtayo (cemiplimab) in patients with locally advanced basal cell carcinoma (BCC) who had progressed on or were intolerant to hedgehog inhibitor (HHI) therapy. The ORR was 31% with a median follow-up of 15 months, including a 6% complete and 25% partial response rate.
Eli Lilly and Company announced Verzenio (abemaciclib) in combination with standard adjuvant endocrine therapy (ET) significantly decreased the risk of breast cancer recurrence by 25% compared to standard adjuvant ET alone for people with HR-/HER2- high-risk early breast cancer. The benefit was consistent across all pre-specified subgroups and was equivalent to a 3.5% difference between arms, 92.2% for Verzenio and 88.7% in the control arm.
Genentech, a Roche company, presented data from three Phase III trials of Tecentriq (atezolizumab) in triple-negative breast cancer (TNBC). First, they presented data from the Phase III IMpassion031 trial of Tecentriq in combination with chemotherapy (Abraxane [albumin-bound paclitaxel; nab-paclitaxel]; followed by doxorubicin and cyclophosphamide) compared to placebo plus chemotherapy. The trial demonstrated a statistically significant and clinically meaningful improvement in pathological complete response (pCR) for people with early TNBC, regardless of PD-L1 expression. pCR was seen in 57.6% of patients receiving the combination, an increase of 16.5% compared to 41.1% in patients treated with placebo plus chemotherapy.
Second was final overall survival (OS) analysis of the Phase III IMpassion130 study of Tecentriq with nab-paclitaxel compared to placebo plus nab-paclitaxel as a first-line treatment for mTNBC. This data was consistent with the first and second interim analyses. The difference in OS between the treatment groups in the intent-to-treat (ITT) populations was not significant. Clinically meaningful improvements in OS were observed with the Tecentriq and nab-paclitaxel group in PD-L1-positive patients. They also indicated that the magnitude of OS improvements with the Tecentriq patients in PD-L1-positive patients was clinically meaningful, with an increase of 7.5 months in median OS with Tecentriq plus nab-paclitaxel compared to placebo plus nab-paclitaxel. But, they noted, the results could not be formally tested because of prespecified statistical testing hierarchy.
And third, data from the Phase III Impassion131 trial of Tecentriq in combination with paclitaxel versus placebo plus paclitaxel as a first-line treatment for patients with metastatic TNBC, did not demonstrate significant improvement for progression-free survival (PFS) in the PD-L1-positive population. The OS data demonstrated a negative trend, but the trial wasn’t powered for the secondary endpoint of OS, plus the OS data were immature at the time of analysis in the PD-L1-positive population, based on 21% of patients with an event.
Novartis announced detailed results from the Phase III COMBI-I trial of spartalizumab in combination with Tafinlar (dabrafenib) and Mekinist (trametinib) compared to Tafinlar and Mekinist alone. The trial did not meet its primary endpoint. The Tafinlar and Mekinist efficacy data represented the longest PFS data observed across multiple Phase III trials.
Seattle Genetics and Genmab A/S presented data from the innovaTV 204 Phase II trial of tisotumab vedotin as monotherapy in previously treated recurrent and/or metastatic cervical cancer. The data showed a 24% confirmed objective response rate (ORR) by independent central review with a median duration of response (DOR) of 8.3 months. Tisotumab vedotin is an ADC of Genmab’s fully human monoclonal antibody specific for tissue factor and Seattle Genetics’ ADC technology that utilizes a protease-cleavable linker covalently attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody.
Precision BioSciences and SpringWorks Therapeutics entered into a clinical trial collaboration deal. They will evaluate Precision’s PBCAR269A, an allogeneic CAR-T cell therapy against B-cell maturation antigen (BCMA) in combination with SpringWorks’ nirogacestat, a gamma secretase inhibitor, in patients with r/r multiple myeloma. It will be an expanded Phase I/IIa trial. Precision launched a Phase I/IIa trial of PBCAR2691 in June.
Exelixis presented positive Phase Ib trial results from a combination of Cabometyx (cabozantinib) and Tecentriq (atezolizumab) in locally advanced or metastatic solid tumors. The combination demonstrated promising preliminary efficacy and a favorable safety profile in patients with clear cell and non-clear cell renal cell carcinoma.
Vaccinex announced topline data from the early manifest treatment arm of its Phase II SIGNAL trial of pepinemab in patients with early manifest and prodromal Huntington’s disease (HD). Although it showed some benefit, it missed both coprimary endpoints. The trial had two co-primary endpoints, a group of two cognitive assessments from the Huntington’s Disease Cognitive Assessment Battery and Clinical Global Impression of Change (CGIC). The trial did not meet pre-specified co-primary endpoints, but the results from both of the two cognitive assessments showed a strong trend for beneficial change. The changes observed suggested changes in planning ability and memory linked with disease progression. Pepinemab (VX15/2503) is a humanized monoclonal antibody that binds and blocks the activity of semaphoring 4D (SEMA4D), an extracellular signaling molecule that regulates the migration and function of immune and inflammatory cells.
ALX Oncology will collaborate with Merck to evaluate ALX148 and Merck’s checkpoint inhibitor Keytruda for head and neck squamous cell carcinoma (HNSCC). ALX148 is a next-generation CD47 blocker. There will be two separate Phase II trials, the first in patients with PD-L1 expressing metastatic or unresectable, recurrent HNSCC. The second will look at the combination with chemotherapy for first-line treatment of patients with metastatic or unresectable, recurrent HNSCC.
Jupiter Orphan Therapeutics received a National Institute on Aging grant of $1.76 million to support a Phase I trial of Jotrol for early-stage Alzheimer’s disease. Jotrol is a proprietary patented formulation with the active ingredient resveratrol, a naturally occurring plant found in small amounts in red wine, red grapes, berries and peanuts.
Frequency Therapeutics completed enrollment of its Phase IIa trial of FX-322 for sensorineural hearing loss (SNHL). It expects full results in the second quarter of 2021. FX-322 is designed to regenerate auditory hair cells to restore hearing function.
Bayer presented new ad hoc analysis from its Phase III ARAMIS trial of Nubeqa (darolutamide) plus androgen deprivation therapy in non-metastatic castration-resistant prostate cancer. The study found that 97.2% of men receiving the combination received the full, planned dose of 600 mg twice a day compared to 98.4% who received ADT alone.
AC Immune and Genentech, a U.S.-based Roche company, announced topline results from the TAURIEL Phase II clinical trial of semorinemab in early Alzheimer’s disease. The drug failed to meet its primary efficacy endpoint, as well as two secondary endpoints. Semorinemab is an anti-Tau antibody. The primary efficacy endpoint was decreasing decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) compared to placebo. The two secondary endpoints were Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13) and Alzheimer’s Disease Cooperative Study Group – Activities of Daily Living Inventory (ADCS-ADL).
Curevo Vaccine released antibody response data from its Phase I trial of CRV-101, its vaccine against shingles. The vaccine demonstrated a robust antibody response against a key component (gE) of the shingles virus at one month after the second vaccination and at one year.
Enterome dosed the first patient in its Phase IIa trial of sibofimloc in patients with Crohn’s disease. Sibofimloc is a first-in-class oral small molecule designed to reduce the inflammatory cascade that underlines Crohn’s disease and remains gut-restricted in order to minimize absorption into the bloodstream.
Afimmune announced the start of the TRIAGE Phase IIb trial of epeleuton in patients with high triglycerides and type 2 diabetes. Epeleuton is a synthetic prodrug of an endogenous downstream metabolite of eicosapentaenoic acid (EPA).
Millendo Therapeutics dosed the first patient in a Phase I trial of MLE-301 for hot flashes and night sweats in menopausal women. MLE-301 is a selective neurokinin 3 receptor (NK3R) antagonist.