Cancer Therapeutics Trends Revealed: Key Advances from ASCO 2022 Highlight Precision Medicine and Novel Modalities

In the next 10 to 20 years, cancer may surpass cardiovascular disease as the leading cause of death globally. How to develop more precise, effective, and efficient cancer diagnosis and treatment methods has been a concern in the industry. At the ongoing 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, several biotechnology and pharmaceutical companies announced the latest progress on therapies under development. The latest clinical data for the antibody-drug conjugate (ADC) Enhertu, released last weekend, demonstrated the potential of this innovative treatment model in transforming breast cancer treatment. Today, the WuXi AppTec content team will share with readers the latest advancements in improving cancer treatments presented at the ASCO conference.

Using the Most Appropriate Treatment for the Right Patients

Recently, Bristol-Myers Squibb (BMS) spent nearly $4.1 billion to acquire Turning Point Therapeutics, a company dedicated to developing precision oncology therapies. This acquisition also highlights the trend in cancer drug development shifting towards precision medicine. Precision treatment involves analyzing the molecular biological characteristics of a patient's tumor to identify targeted therapies that match the tumor’s biomarkers. Compared with traditional chemotherapy and radiation therapy, these treatments often exhibit higher efficacy while having fewer toxic side effects. At the ASCO Annual Meeting, multiple studies also demonstrated the power of this strategy.

100% Complete Response Rate! Biomarker-Guided Immunotherapy Promises to Change the Treatment Paradigm for Rectal Cancer

In a phase 2 clinical trial presented at the ASCO Annual Meeting, researchers from Memorial Sloan Kettering Cancer Center used the PD-1 inhibitor dostarlimab in patients with locally advanced rectal cancer carrying mismatch repair deficiency (dMMR). The current standard treatment for this patient population is neoadjuvant chemoradiotherapy plus surgical resection. Although this strategy has a high cure rate, it comes with significant side effects, including infertility, bladder dysfunction, and permanent colostomy.

Among 12 patients who received treatment and were followed up for at least six months, all 12 achieved complete remission, meaning no trace of cancer was detected using various tests. The study has been published in The New England Journal of Medicine. As of the publication date, no patient required subsequent radiotherapy, chemotherapy, or surgery, and no patient experienced disease progression or recurrence, with the longest duration of complete remission reaching 25 months. Additionally, no adverse events of grade 3 or higher were observed among the patients.

Although this study involved a small number of patients and had a short follow-up period, and the results still need to be confirmed in clinical trials with longer follow-up times and larger patient populations, a commentary article published in The New England Journal of Medicine pointed out that this study offers us a glimpse into the future of a "revolutionary treatment model."

Treatment of Non-Small Cell Lung Cancer: KRAS Inhibitors Significantly Shrink Central Nervous System Metastases

Last year, the approval of KRAS G12C inhibitor Lumakras by the FDA not only marked a breakthrough in targeting the previously "undruggable" KRAS mutation but also provided patients with non-small cell lung cancer (NSCLC) carrying the KRAS G12C mutation with a more effective and less toxic precision therapy. Currently, multiple KRAS G12C inhibitors are in clinical development. At the ASCO Annual Meeting, Mirati Therapeutics presented the latest data on its KRAS G12C inhibitor adagrasib. The trial results showed that among 19 NSCLC patients with untreated active central nervous system (CNS) metastases, adagrasib achieved an intracranial response rate of 32%, with three patients achieving complete responses. The intracranial disease control rate was 84%.

In NSCLC patients harboring the KRAS G12C mutation, 27% to 42% develop central nervous system metastases, and these patients typically have a median overall survival of only 5 months, representing a significant unmet need. The data demonstrate that adagrasib can provide clinically meaningful intracranial relief, offering another example of biomarker-based precision therapy.

At the recently concluded WuXi AppTec Healthcare Industry Forum, Professor Harold Burstein from Harvard Medical School pointed out that the future opportunities of biomarkers have excited large pharmaceutical companies and brought hope for the early diagnosis of cancer. Through biomarker testing, oncologists have gained more knowledge about cancer, which has also changed their overall perspective on cancer treatment.

Beyond developing precision therapies for niche patient populations, a wave of research into new molecular modalities is also on the rise. As one of the new molecular modalities, CAR-T therapy has expanded rapidly in recent years, with the next generation of CAR-T therapies showcasing their potential at the ASCO conference.

CAR-T Therapy: New Cell Types and New Designs

Currently, six CAR-T therapies have been approved by the FDA for the treatment of various blood cancers. However, the widespread application of autologous CAR-T cell therapy still faces significant challenges, such as a complex manufacturing process and potential toxic side effects like cytokine release syndrome. At the ASCO Annual Meeting, several companies presented clinical trial results of next-generation CAR-T therapies, showcasing improvements to CAR-T cell therapy from different perspectives.

Off-the-Shelf γδ T-Cell Therapy Achieves 75% Complete Response Rate

Adicet Bio Announces Updated Phase 1 Clinical Trial Results for Potential “First-in-Class” γδ T Cell Therapy ADI-001. This is an off-the-shelf cell therapy created by genetically engineering allogeneic γδ T cells to express a chimeric antigen receptor (CAR) targeting the CD20 antigen. It can target malignant B cells through the anti-CD20 CAR and endogenous cytotoxic receptors expressed by γδ T cells. Off-the-shelf cell therapies are one of the strategies to overcome the complex manufacturing process and long cycle associated with autologous CAR-T therapies.

Trial results showed that, in eight patients with non-Hodgkin lymphoma who had received multiple prior therapies, ADI-001 demonstrated a 75% overall response rate and a 75% complete response rate. Among three patients who had previously been treated with CD19-targeted CAR-T therapy and experienced relapse, ADI-001 achieved a 100% complete response rate. Specific data can be found in the table below:

▲ Phase 1 Clinical Trial Data of Different Doses of ADI-001 (Image Source: Adicet Bio Company Official Website)

Carrying a unique CAR structure, BCMA-targeted cell therapy achieves a 100% overall response rate

Arcellx Announces Initial Results of CART-ddBCMA Therapy Targeting BCMAArcellx has announced preliminary results of its CART-ddBCMA therapy targeting BCMA. The uniqueness of CART-ddBCMA lies in the use of a synthetic peptide called the D domain instead of an antibody fragment targeting BCMA for the CAR expressed on the T-cell surface. Compared to traditional antibody fragments, it is smaller and more stable. Preclinical studies have shown higher transfection efficiency and higher expression levels on the cell surface, features that may allow for treatment with a lower dose, reducing toxic side effects. Moreover, the design of the D domain reduces sustained signaling caused by CAR aggregation, thereby decreasing premature T-cell exhaustion.

▲CART-ddBCMA uses a structurally simpler D protein domain to bind with BCMA (Image source: Arcellx official website)

Trial results showed that in the clinical trial for treating relapsed/refractory multiple myeloma patients, with a median follow-up time of 12.1 months, CART-ddBCMA achieved a 100% overall response rate (n=31), with 71% of patients reaching complete response or stringent complete response, and 94% of patients achieving a response better than very good partial response. 81% of patients treated for more than 12 months reached complete response or stringent complete response.

In terms of safety, among the 31 patients, only one case experienced cytokine release syndrome of grade 3 or higher, and another case experienced neurotoxicity of grade 3 or higher.

Developing more efficient innovative therapies is undoubtedly an important way to improve cancer treatment, and earlier detection and treatment of cancer are also effective means to improve patient outcomes. Let's take a look at the progress in this area.

Earlier Diagnosis, Earlier Treatment

When cancer is at an early stage, it can be cured through various treatments such as surgery. However, once metastasis occurs, especially distant metastasis, the patient's prognosis will significantly decline. Therefore, one of the main directions in cancer treatment is diagnosing patients at an earlier stage of the disease and intervening. The example mentioned above of PD-1 inhibitor treatment for locally advanced rectal cancer also reflects the strategy of applying immunotherapy to patients with earlier-stage cancer.

Dostarlimab has received accelerated approval from the FDA for the treatment of patients with recurrent or advanced solid tumors carrying mismatch repair deficiency. However, in clinical trials, the complete response rate of dostarlimab was only 9.1% among patients with mismatch repair deficiency solid tumors that included various cancer types. Due to significant differences in the enrolled patients, the results of these two clinical trials cannot be directly compared. Nevertheless, industry experts suggest that using immune checkpoint inhibitors such as anti-PD-1 antibodies at an earlier stage could theoretically yield better outcomes, as patients’ immune systems are likely healthier and may respond better to immune checkpoint inhibitors.

At the ASCO annual meeting, several biopharmaceutical companies also announced the outcomes of treatments administered at earlier stages of cancer. For instance, MSD disclosed the results of a Phase 3 clinical trial for its key PD-1 inhibitor, Keytruda, as an adjuvant therapy for patients with Stage IIB or IIC melanoma. At a median follow-up time of 27.4 months, compared to placebo, Keytruda significantly improved the distant metastasis-free survival of patients (HR=0.64, 95% CI, 0.47-0.88, p=0.0029). Additionally, Keytruda reduced the risk of cancer recurrence compared to placebo (HR=0.64, 95% CI, 0.50-0.84).

Based on these results, the FDA has approved Keytruda for expanded use. The standard treatment for patients with Stage IIB or IIC melanoma was previously observation after surgery; this approval provides them with a new adjuvant treatment option.

In addition to early treatment, early detection of cancer is equally important. At the WuXi AppTec Healthcare Industry Forum, Dr. Harold Burstein also mentioned that current early cancer screening is still limited to a few types of cancer, such as colorectal cancer. In the future, if molecular testing can be applied to esophageal cancer, pancreatic cancer, and ovarian cancer, it could bring about a revolution.

An important research direction for the early diagnosis of cancer is liquid biopsy, which detects biomarkers in the blood. At the ASCO Annual Meeting, Caris Life Sciences launched a liquid biopsy test called Caris Assure. Its uniqueness lies in the simultaneous analysis of whole exome and whole transcriptome of up to 22,000 genes from a single blood sample. By analyzing both DNA and RNA at the same time, this test can capture more molecules that provide tumor information, improve detection performance, and offer patients and doctors a more comprehensive molecular profile of the tumor.

In the preliminary validation study, this liquid biopsy achieved over 95% sensitivity for genetic variants with variant frequencies exceeding 0.5%, while maintaining over 99.99% specificity.

Tomorrow, the ASCO Annual Meeting will come to an end. At this year's meeting, we have witnessed the efforts of researchers in making cancer diagnosis and treatment more precise, effective, and efficient. We look forward to these achievements reaching patients soon to bring them benefits.

References:

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[2] OriCell Reports OriCAR-017 Phase I POLARIS study Data in Oral Presentation at American Society of Clinical Oncology(ASCO) Annual Meeting 2022. Retrieved June 6, 2022, from https://www.prnewswire.com/news-releases/oricell-reports-oricar-017-phase-i-polaris-study-data-in-oral-presentation-at-american-society-of-clinical-oncologyasco-annual-meeting-2022-301561427.html

[3] Adicet Bio Reports Emerging Data from ADI-001 Phase 1 Trial at the American Society of Clinical Oncology Annual Meeting. Retrieved June 6, 2022, from https://investor.adicetbio.com/news-releases/news-release-details/adicet-bio-reports-emerging-data-adi-001-phase-1-trial-american

[4] Arcellx Presents Continued Robust Long-Term Responses from its CART-ddBCMA Phase 1 Expansion Trial in Patients with Relapsed or Refractory Multiple Myeloma at the 2022 ASCO Annual Meeting. Retrieved June 6, 2022, from https://www.prnewswire.com/news-releases/arcellx-presents-continued-robust-long-term-responses-from-its-cart-ddbcma-phase-1-expansion-trial-in-patients-with-relapsed-or-refractory-multiple-myeloma-at-the-2022-asco-annual-meeting-301561200.html

[5] Gracell Biotechnologies to Present Updated Clinical Data on BCMA/CD19 Dual-Targeting CAR-T GC012F for Relapsed/Refractory Multiple Myeloma at 2022 ASCO Annual Meeting. Retrieved June 6, 2022, from https://ir.gracellbio.com/news-releases/news-release-details/gracell-biotechnologies-present-updated-clinical-data-bcmacd19

[6] Merus Presents Clinical Data on Zenocutuzumab (Zeno) in NRG1-fusion (NRG1+) Cancer at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting (Oral Abstract). Retrieved June 6, 2022, from https://ir.merus.nl/news-releases/news-release-details/merus-presents-clinical-data-zenocutuzumab-zeno-nrg1-fusion-nrg1

[7] New Late-Breaking Data on Investigational Adagrasib Show Regression of Central Nervous System (CNS) Metastases in Patients with KRASG12C-mutated Non-Small Cell Lung Cancer (NSCLC) with Active, Untreated CNS Metastases. Retrieved June 6, 2022, from https://ir.mirati.com/press-releases/press-release-details/2022/New-Late-Breaking-Data-on-Investigational-Adagrasib-Show-Regression-of-Central-Nervous-System-CNS-Metastases-in-Patients-with-KRASG12C-mutated-Non-Small-Cell-Lung-Cancer-NSCLC-with-Active-Untreated-CNS-Metastases/default.aspx

[8] Cercek et al., (2022). PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. NEJM, DOI: 10.1056/NEJMoa2201445

[9] Menarini Group and Radius Health, Inc. present a subgroup analysis from the elacestrant pivotal phase 3 EMERALD clinical trial at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting. Retrieved June 6, 2022, from https://www.globenewswire.com/news-release/2022/06/06/2456838/31149/en/Menarini-Group-and-Radius-Health-Inc-present-a-subgroup-analysis-from-the-elacestrant-pivotal-phase-3-EMERALD-clinical-trial-at-the-2022-American-Society-of-Clinical-Oncology-ASCO-.html

[10] Immutep Reports Positive Overall Response Rate in its Phase II Clinical Trial in 1st line NSCLC for PD-L1 All-Comers. Retrieved June 6, 2022, from https://www.globenewswire.com/news-release/2022/06/03/2456177/0/en/Immutep-Reports-Positive-Overall-Response-Rate-in-its-Phase-II-Clinical-Trial-in-1st-line-NSCLC-for-PD-L1-All-Comers.html

[11] Adjuvant Treatment With Merck’s KEYTRUDA® (pembrolizumab) Demonstrates Statistically Significant & Clinically Meaningful Improvement in Distant Metastasis-Free Survival in Patients With Resected Stage IIB or IIC Melanoma in Phase 3 KEYNOTE-716 Trial. Retrieved June 6, 2022, from https://www.merck.com/news/adjuvant-treatment-with-mercks-keytruda-pembrolizumab-demonstrates-statistically-significant-clinically-meaningful-improvement-in-distant-metastasis-free-survival-in-patients-with-r/

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