Optellum, a lung-health medical technology startup based in the United Kingdom, and the Lung Cancer Initiative at Johnson & Johnson in August have announced an ongoing partnership. The 2 companies plan to use Optellum’s artificial intelligence (AI)-based decision support software in an effort to increase lung cancer survival rates via disease prevention and early intervention.

In March 2021, the FDA gave clearance to Optellum’s Virtual Nodule Clinic, an AI-powered clinical decision support software for pulmonologists and radiologists treating patients with small lesions that could represent early-stage lung cancer.

 This is the first time the FDA has cleared such an application of AI decision support for early lung cancer diagnosis.

The software incorporates an AI-powered digital biomarker that is based on neural networks and imaging analytics. Virtual Nodule Clinic identifies and tracks patients at elevated risk and assigns a Lung Cancer Prediction score to lung nodules that may be malignant and are usually detected in chest CT scans.

In the pivotal clinical study measuring physicians’ average accuracy in classifying nodules as malignant or benign, the AI was associated with a statistically significant improvement in accuracy in all readers.

 Investigators observed an average improvement of 6.85 area under the curve (AUC) points (

<.001) overall and an improvement of 2.4 to 12.1 AUC points for individual physicians. In addition to improved diagnostic accuracy, use of the AI resulted in more consistency among physicians.

In an independent validation study, investigators compared the AI’s risk-prediction model vs the Brock University model recommended in UK guidelines. There were 1397 nodules in 1187 patients, of which 234 nodules in 229 (19.3%) patients were cancer. The AUC for Virtual Nodule Clinic was 89.6% (95% CI, 87.6%-91.5%) compared with 86.8% (95% CI, 84.3%-89.1%) for the Brock model (

Investigators found that 24.5% of nodules scored below the lowest cancer nodule score with the AI compared with 10.9% using the Brock score. Using predefined thresholds, investigators concluded that the AI delivered 1 (0.4%) false positive while the Brock model delivered 6 (2.5%). Specificity statistics were similar between the 2 models.

Physicians can use the software to develop accurate early diagnosis and optimal treatment decisions. The companies hope to improve survival rates by treating patients earlier, even at the precancerous stage.

“I believe the next step in lung cancer diagnosis and treatment is seeing the emerging new technologies coming together. AI is key to enabling integration of imaging, clinical, and molecular data—such as liquid biopsies—to diagnose disease even earlier,” Sam Janes, MD, head of the Respiratory Research Department at UCL Hospitals, vice-chair of the UK National Clinical Reference Group for Lung Cancer, and member of the Optellum Medical Advisory Board, said in a news release. “This convergence of technologies has tremendous potential to help physicians prevent, intercept, and ultimately cure patients with early-stage lung cancer.”

Lung cancer is the leading cause of cancer deaths and is the second-most common cancer in the United States—annually, more people die of lung cancer than of colon, breast, and prostate cancers combined. The American Cancer Society predicted 131,880 deaths from lung cancer in 2021, with 119,100 new diagnoses in men and 116,660 new diagnoses.

The 5-year survival rate for non-small cell lung cancer (NSCLC), the most common form of the disease, is 25% for all disease stages. However, survival is significantly better when the disease is detected early. The 5-year relative survival rate is 63% for localized disease compared with just 7% for metastatic NSCLC.

This move is part of Johnson & Johnson’s larger efforts to address lung cancer. In 2018, the company announced that it would fund a Lung Cancer Center at Boston University (BU) Medical Center led by Avrum Spira, MD, professor of medicine, pathology and bioinformatics at BU and global head of the company’s Lung Cancer Initiative.

“This collaboration is a significant milestone for Optellum,”Václav Potěšil, PhD, Optelum founder and CEO said in the news release. “It brings us one step closer to our vision of redefining early lung cancer treatment by helping every clinician, in every hospital to make the right decisions and provide their patients the best chance to fight back.”

Optellum Announces Strategic Collaboration with the Lung Cancer Initiative at Johnson & Johnson, Applying Ai To Transform Early Lung Cancer Treatment. News release. Optellum. August 18, 2021. September 1, 2021. https://bit.ly/3tordj9

Optellum Receives Fda Clearance for the World’s First Ai-Powered Clinical Decision Support Software for Early Lung Cancer Diagnosis. News release. Optellum. March 23, 2021. Accessed September 1, 2021. https://optellum.com/2021/03/fda-clearance.

Vachani A, Massion PP, Munden RF, et al., Imaging AI/”Radiomics” decision support improves physicians’ stratification of indeterminate pulmonary nodules: An MRMC study presented to the Baldwin DR, Gustafson J, Pickup L, et al. External validation of a convolutional neural network artificial intelligence tool to predict malignancy in pulmonary nodules. 

. 2020;75(4):306-312. doi:10.1136/thoraxjnl-2019-214104

American Cancer Society National Lung Cancer Roundtable (NLCRT) 2020. https://vimeo.com/487367357

American Cancer Society. Key Statistics for Lung Cancer. Revised January 12, 2021. Accessed September 3, 2021. https://www.cancer.org/content/cancer/en/cancer/lung-cancer/about/key-statistics.html

American Cancer Society. Lung Cancer Survival Rates Revised January 29, 2021. Accessed September 3, 2021. https://www.cancer.org/cancer/lung-cancer/detection-diagnosis-staging/survival-rates.html

Articles

Optellum and the Lung Cancer Initiative at Johnson & Johnson plan to use Optellum’s artificial intelligence-based decision support software in an effort to increase lung cancer survival rates via disease prevention and early intervention.

Optellum, Johnson & Johnson Launch Strategic Collaboration in Lung Cancer

Zanidatamab is being combined with tucatinib (Tukysa) and capecitabine in a new cohort of a phase 1 trial (NCT02892123) of patients with locally advanced (unresectable) and/or metastatic HER2-positive breast cancer, according to an announcement by Zymeworks, Inc., the developer of the agent.

“Recent clinical trials have demonstrated the benefit of combining tucatinib with trastuzumab [Herceptin] and chemotherapy in patients with metastatic HER2-positive breast cancer,” said Neil Josephson, MD, interim chief medical officer at Zymeworks. “Given the antitumor activity of zanidatamab observed across a range of HER2-overexpressing tumors and preclinical studies demonstrating improved anti-tumor activity of zanidatamab compared to trastuzumab, we believe the combination of zanidatamab with tucatinib and chemotherapy has the potential to be an impactful treatment for patients with advanced HER2-positive breast cancer, including those with brain metastases.”

As of July 28, 2021, the first patient has been dosed in this new cohort. The study’s estimated primary completion date is January 31, 2022.

Zanidatamab is a bispecific antibody that binds to HER2 across expression levels and has the following mechanisms of action: formation of receptor clusters, resulting in receptor internalization and downregulation that affect signal transduction; and potently activates the immune system to elicit antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity.

In the first-in-human, 3-part trial, investigators are evaluating the efficacy, safety, and tolerability, as well as pharmacokinetics, of zanidatamab alone or in combination with select chemotherapy regimens in patients with locally advanced (unresectable) and/or metastatic HER2-expressing cancers.

In part 1 of the trial, zanidatamab will be tested at increasing doses to determine the maximum-tolerated dose (MTD), the optimal biological dose (OBD), and/or other recommended doses in up to 7 dose-specific cohorts.

Part 2 of the trial will continue to explore efficacy, safety, and tolerability of zanidatamab in this patient population in up to 5 separate disease-specific cohorts, which will include the MTD, OBD, or recommended dose identified in part 1.

In part 3 of the study, zanidatamab will be combined with the following agents: paclitaxel, vinorelbine, or capecitabine alone or with tucatinib.

To be eligible for enrollment, patients with locally advanced (unresectable) and/or metastatic HER2-expressing cancer have to have progressed on or are ineligible to receive all standard therapies. In part 3 of the trial, patients must have progressed on 1 to 3 prior systemic chemotherapy regimens.

Those who received experimental therapies within 4 weeks before first zanidatamab dose, anthracyclines within 90 days before first dose, history of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in drug formulation, have peripheral neuropathy higher than grade 2, or clinically significant interstitial lung cancer, among other factors, are excluded from enrollment.

The coprimary end points are dose-limiting toxicities and treatment-related adverse events; secondary end points include serum concentrations, detectable anti-drug antibodies, objective response rate (ORR) via RECIST v1.1 criteria, progression-free survival via RECIST v1.1 criteria, and safety.

“This new study cohort complements our ongoing trials with zanidatamab in combination with other standard-of-care treatment regimens and supports our goal of establishing zanidatamab as the foundational therapy for HER2‑expressing cancers,” Josephson concluded.

Previously, the FDA granted breakthrough therapy designation to zanidatamab as a potential therapy for patients with previously treated HER2 gene-amplified biliary tract cancer (BTC). The agent also has 2 fast track designations to zanidatamab; one is for use as a single agent for patients with refractory BTC, while the second is for use in combination with standard chemotherapy for the first-line treatment of patients with gastroesophageal adenocarcinoma.

 is based on an ongoing phase 1 study (NCT02892123) of zanidatamab in patients with locally advanced, unresectable and/or metastatic HER2-expressing cancers, including BTC. 

Here, the confirmed objective response rate was 33%

 and the disease control rate was 61% when zanidatamab was used as a monotherapy.

 These rates were 54% and 79%, respectively, when zanidatamab was given in combination with chemotherapy.

Tucatinib is currently approved by the FDA for use in combination with trastuzumab and capecitabine for the treatment of adult patients with unresectable advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have received at least 1 prior therapy.

Zymeworks announces first patient with advanced her2-positive breast cancer dosed with zanidatamab in combination with Tukysa (tucatinib) and chemotherapy. News release. Zymeworks Inc. July 28, 2021. Accessed July 28, 2021. 

Trial of ZW25 (Zanidatamab) in Patients With Advanced HER2-expressing Cancers. ClinicalTrials.gov. Last Updated August 4, 2021. Accessed August 23, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02892123?term=Zanidatamab&draw=2&rank=4

Meric-Bernstam F, Hamilton EP, Beeram M, et al. Zanidatamab (ZW25) in HER2-expressing gastroesophageal adenocarcinoma (GEA): results from a phase I study. 

. 2021; 39(suppl 3):164. doi:10.1200/JCO.2021.39.3_suppl.164

Zanidatamab is being combined with tucatinib and capecitabine in a new cohort of a phase 1 trial of patients with locally advanced and/or metastatic HER2-positive breast cancer.

Zanidatamab Plus Tucatinib/Capecitabine Is Being Tested in Advanced HER2+ Breast Cancer

The autologous CAR T-cell therapy P-PSMA-101 elicited robust antitumor responses in patients with metastatic castration-resistant prostate cancer (mCRPC), according to preliminary findings from the phase 1 P-PSMA-101-001 trial (NCT04249947) that were virtually presented during the 6th Annual CAR-TCR Summit.

A total of 9 patients with mCRPC had been enrolled to the study; 5 of these patients received the product at Dose A, which was a single treatment of 0.25 x 10E6 cells/kg (an average of 20 million cells), and 4 patients were given the product at Dose B, which was a single treatment of 0.75 x 10E6 cells/kg (an average of 60 million cells). All participants were given a lymphodepletion regimen comprised of fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2.

Results indicated that 5 patients experienced measurable declines in prostate-specific antigen (PSA) levels. Additionally, 3 patients experienced a greater than 50% decline in PSA levels and had concordant improvements in PSMA-PET imaging. Notably, 1 patient showcased evidence suggestive of complete tumor elimination and continues to experience a response that has persisted for more than 5 months.

“This innovative Poseida PSMA-directed CAR T-cell platform has demonstrated a robust antitumor response in patients with mCRPC,” Susan F. Slovin, MD, PhD, associate vice chair of Academic Administration at Memorial Sloan Kettering Cancer Center and trial investigator, stated in a press release. “This is the first time that I have seen such impressive responses with an immunotherapy product. The responses of my patients in the trial are far beyond my expectations.”

P-PSMA-101 was designed to target prostate-specific membrane antigen, which is expressed on mCRPC cells.

 The agent was developed using the piggyBac DNA Modification System, which manufactures products with a higher percentage of stem cell memory cells that can reconstruct T-cell subsets like effector T cells, which have a key role in tumor elimination.

One of the goals of the open-label, multicenter, 3+3 dose-escalating phase 1 trial was to identify the optimal dose of P-PSMA-101 that can safely be given to patients with mCRPC.

 Patients needed to have mCRPC that continued to progress despite prior treatment for advanced disease, an ECOG performance status of 0 or 1,

 and acceptable organ function within predetermined parameters. They could not still be experiencing serious toxicities from previous therapies.

The primary end points of the trial were to evaluate the safety of the CAR T-cell therapy, determine the maximum-tolerated dose, and examine the efficacy of the product. Participants were heavily pretreated, having received an average of 6 previous lines of therapy with a median time of 6.4 years since diagnosis.

FDA placed a clinical hold on the P-PSMA-101-001 trial

 following notification of a patient death.

 The patient had previously progressed on various anticancer therapies prior to receiving treatment with the CAR T-cell product in late July 2020 and was reported to have had normal laboratory results after the first week of treatment; at that time point, no clinical symptoms indicative of an adverse effect (AE) were reported.

The patient, however, went on to miss his follow-up visits that were scheduled for days 10 and 14. During that time, the patient went on to experience symptoms that resulted in hospitalization. On day 19 following treatment with the CAR T-cell product, the patient died of hepatic failure. The direct cause of the hepatic failure had not been confirmed.

Specifically, the patient had presented with symptoms that proved to be consistent with macrophage activation syndrome (MAS), which is a serious overactivation of the immune system that has previously been associated with CAR T-cell products. However, MAS can also be caused by other events like autoimmune disease or infection. The patient also experienced blurred vision and had a diagnosis of uveitis. The severe toxicity was found to potentially be linked with P-PSMA-101 but warranted further investigation.

 in November 2020, and Poseida Therapeutics announced plans to resume the trial immediately having agreed to make amendments to the protocol to increase patient compliance and safety.

 Some of the modifications had to do with inclusion and exclusion criteria and frequency of monitoring and laboratory testing.

The CAR T-cell therapy was found to have favorable safety and tolerability in this population. Beyond the case of MAS that was exacerbated by patient non-compliance, only 3 cases of potential cytokine release syndrome were reported. However, all these cases were grade 1 or 2 and were managed effectively with early treatment. Notably, no neurotoxicity was reported with the product by the data cutoff date.

“We are excited about the preliminary data from our phase 1 trial of P-PSMA-101, which provides further evidence of the effectiveness of our CAR-T platform for solid tumor cancers,” Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc., stated in a press release. “To date, other CAR-T therapeutics have not had much success outside of hematologic malignancies. The deep and durable responses in our trial demonstrate that CAR-T products have the potential to work well against solid tumors, even at low doses, when using the appropriate technology platform.”

Poseida Therapeutics presents preliminary results from phase 1 trial of P-PSMA-101 at the 6th Annual CAR-TCR Summit. News release. Poseida Therapeutics, Inc. August 31, 2021. Accessed August 31, 2021. 

Poseida Therapeutics announces dosing of first patient on phase 1 clinical trial of P-PSMA-01 autologous CAR-T for metastatic castration-resistant prostate cancer. News release. Poseida Therapeutics, Inc. May 20, 2020. Accessed August 31, 2021. 

A phase I study of P-PSMA-01 CAR T-cell therapy in men with metastatic castration-resistant prostate cancer. Memorial Sloan Kettering Cancer Center. Accessed August 31, 2021. 

P-PSMA-01 CAR-T cells in the treatment of subjects with metastatic castration-resistant prostate cancer (mCRPC). ClinicalTrials.gov. Updated July 13, 2020. Accessed August 31, 2021. 

https://www.clinicaltrials.gov/ct2/show/NCT04249947

Gergen MJ. Form 8-L: Poseida Therapeutics, Inc. United States Securities Exchange Commission. August 17, 2020. Accessed August 31, 2021. 

Poseida Therapeutics announces clinical hold lifted on phase I autologous CAR-T study in prostate cancer. News release. Poseida Therapeutics, Inc. November 2, 2020. Accessed August 31, 2021. 

The autologous CAR T-cell therapy P-PSMA-101 elicited robust antitumor responses in patients with metastatic castration-resistant prostate cancer, according to preliminary findings from the phase 1 P-PSMA-101-001 trial that were virtually presented during the 6th Annual CAR-TCR Summit. 

Pipeline Report: September 2021

Articles

Optellum, Johnson & Johnson Launch Strategic Collaboration in Lung Cancer

Zanidatamab Plus Tucatinib/Capecitabine Is Being Tested in Advanced HER2+ Breast Cancer