ASH 2023: MRD Highlights in BioPharma Drug Development

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Clinically Actionable Insights: A Q&A with Dr. Luciano Costa on the Final Analysis of MASTER

Image of Dr. Luciano Costa
Susan Bobulsky

Luciano Costa, MD, PhD, Associate Director for Clinical Research at O’Neal Comprehensive Cancer Center & Susan Bobulsky, SVP, Diagnostics, clonoSEQ

In 2021, Susan Bobulsky sat down with Dr. Luciano Costa to learn about the initial results from the phase 2 MRD response-Adapted Sequential ThERapy (MASTER) trial. The trial evaluated daratumumab (Darzalex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Dara-KRd) as induction therapy in patients with newly diagnosed multiple myeloma (MM), followed by autologous stem cell transplant (ASCT) and up to 8 cycles of Dara-KRd consolidation. Measurable residual disease (MRD) status measured by clonoSEQ® was used to modulate treatment duration and cessation.

The findings represented a huge step forward for understanding how we should be personalizing treatment decisions based on MRD-negative status. Specifically, it examined the cessation of therapy in newly diagnosed multiple myeloma patients who showed deep MRD-negative responses to treatment. Data from the final analysis of MASTER with extended follow-up time were published earlier this fall, so we checked back in with Dr. Costa to discuss what else we’ve learned and hear his perspective on how the findings might be implemented into practice.

1. Can you speak to the additional findings from the MASTER final analysis vs. the initial publication? What else have we learned?

With the extended follow-up (median 42.2 months vs. 23.8 months in the initial publication) we learned a few important things. Perhaps the most important is that most patients with standard risk multiple myeloma (MM) will achieve and sustain MRD-negative response without ongoing therapy. A longer follow-up gives us more confidence in this approach. We could also demonstrate that the use of MRD-adapted treatment modulation appears to negate the prognostic impact of MRD after transplant. This is a very important step to demonstrate the utility of adjusting therapy to depth of response.

2. Can you share your insights on the subset of patients whose outcomes were better with sustained MRD negativity at 10-6?

With longer follow-up we could also examine the impact of sustained (12 months) MRD negativity. We demonstrated that among patients with sustained MRD<10-5, those with sustained MRD<10-6 have better progression free survival (PFS) than those with sustained MRD between 10-5 and 10-6. This further supports the notion that the lower the threshold for “positivity,” the better the assay will be able to identify patients with exquisitely good prognosis.

3. How have you implemented the findings from this study into clinical practice and how do you feel others can implement findings?

That has been an important practical lesson from this study, that sequential MRD assessment can be incorporated in the management of patients with NDMM and can be employed to inform depth of response. In an era where most patients will achieve responses deep enough to render serum and urine paraprotein unquantifiable, MRD becomes the only way to quantitatively track disease burden. We have fully incorporated this tool in our patient management, and we routinely use this information to decide on post-transplant consolidation and to defer subsequent therapy in patients without ultra-high-risk MM who have sustained MRD negativity.

4. We at Adaptive have been so thrilled to see the first published results from a trial in MM where MRD is used not only as a correlative but as an actionable parameter. In what other ways do you think we should be studying MRD to continue to generate actionable insights?

Absolutely. Like others, we have an ongoing trial employing experimental, enhanced consolidation for patients with MRD>=10-5 after ASCT.  We also have the ongoing MASTER-2 trial, asking different questions for patients who are MRD-positive and MRD-negative after completion of induction. If successful, this can solidify MRD assessment post induction as a parameter to decide on subsequent therapy. Other trials are underway on the same premise. MRD is not a perfect biomarker, and we don’t have a perfect biomarker in any cancer. But I have no doubt it is the best indicator of treatment success and the strongest prognostic factor. The notion of asking different treatment questions to populations with different prognoses and/or achieving different levels of response was always a natural element of developing therapies for malignancies we now consider curable. We should do the same for MM.

5. What are you most looking forward to seeing at the upcoming ASH meeting?

For MM, I think this will be an ASH about better understanding MM and our treatments rather than an ASH about new treatments. There is an explosion of good work geared towards understanding mechanisms of resistance to immunotherapy, both intrinsic to the clonal cells and related to the immune environment. This will be crucial as we learn how to best choose and sequence the many available new therapies.


clonoSEQ® is available as an FDA-cleared in vitro diagnostic (IVD) test service provided by Adaptive Biotechnologies to detect minimal residual disease (MRD) in bone marrow from patients with multiple myeloma or B-cell acute lymphoblastic leukemia (B-ALL) and blood or bone marrow from patients with chronic lymphocytic leukemia (CLL). clonoSEQ is also available for use in other lymphoid cancers and specimen types as a CLIA-validated laboratory developed test (LDT). For important information about the FDA-cleared uses of clonoSEQ including test limitations, please visit clonoSEQ.com/technical-summary

Immune Medicine in Action: How Adaptive Immunosequencing Helped Validate a Personalized Vaccine Trial in PDAC

Harlan Robins

Harlan Robins, PhD, Chief Scientific Officer and Co-founder

Over the past decade, the rapid advancement of immunotherapies has been revolutionary in several cancers. However, pancreatic ductal adenocarcinoma, or PDAC, has been described as a “cold tumor” where immunosuppression results in low T-cell infiltration and poor treatment responses to immunotherapy. PDAC is an aggressive form of cancer with an average 5-year survival rate of less than 10% and a nearly 90% rate of recurrence.

In a 2017 publication1, Dr. Vinod Balachandran, surgical oncologist at Memorial Sloan Kettering Cancer Center (MSKCC), worked with Adaptive to leverage our T-cell receptor beta (TCRB) sequencing assay on research that found long-term survivors of PDAC could mount spontaneous T-cell responses against tumor-specific neoantigens not shared among patients. From there, he hypothesized that personalized mRNA vaccines could provide clinical benefit.

Results from Balachandran’s Phase 1 study2 of a personalized mRNA vaccine were recently published in Nature, and demonstrated a potential breakthrough for PDAC treatment. Again, Adaptive Immunosequencing provided critical insight into the T-cell response elicited by the vaccine, and its correlation with delayed disease recurrence.

T-Cell Clonal Expansion as a Potential Prognostic Biomarker

To investigate the diversity and specificity of T-cell clonal expansion generated by the mRNA vaccine, the study authors developed a mathematical method using Adaptive Immunosequencing that analyzed peripheral blood pre- and post-vaccination. They identified vaccine-induced expanded clones in 8 of 8 responders and 1 of 8 non-responders, serving as a potential prognostic biomarker of disease recurrence. Adaptive Immunosequencing provided a quantitative and molecular characterization of T-cell clones, allowing for identification of vaccine vs immune checkpoint inhibitor (ICI) expanded T cells and uncovering a T-cell response in a non-responder that was missed by ELISpot (a traditional functional assay).  

About the Study

Balachandran and his team of MSKCC researchers shipped samples of PDAC patient tumors to scientists at BioNTech and Genentech. The tumors were sequenced to identify individual patient neoantigens to create a patient-specific vaccine, autogene cevumeran.

The vaccine was given in combination with an ICI and chemotherapy after surgery. At 18-months median follow-up, half of those treated (eight patients) who had T-cell responses to autogene cevumeran were recurrence-free, with a significantly longer recurrence-free survival compared to 13.4 months median in eight non-responders. 

A Critical Tool in Drug Development

This study highlights how Adaptive Immunosequencing can assess response and provide quantitative data to inform the development of new vaccines that can have significant impact on patient lives. This is the power of Immune Medicine in action.



References:

  1. Balachandran VP, Leach SD, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature (2017)
  2. Rojas LA, Balachandran VP, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature (2023)

Adaptive MRD Chief Commercial Officer Nitin Sood Shares How His Personal Journey Has Shaped His Career Path

Nitin Sood

Nitin Sood, Chief Commercial Officer, MRD

Here at Adaptive, putting the patient first is a core value—a philosophy that deeply resonates with me. Similar to many of my fellow Adapters, my inspiration is personal and I’m excited by the tremendous potential impact we can have on human lives through the work we’re doing in our Immune Medicine and MRD businesses.

Growing up in New Delhi, India, my father worked for a large pharmaceutical company, while my mother was a physician and a professor of medicine. Some of my earliest memories are of accompanying her to medical school classes, which inspired me to eventually pursue a PhD in molecular biology and biochemistry.

My studies brought me to the U.S., where my interests shifted towards computer science and after school, I landed a role where I could apply both my software engineering and molecular biology training. At first, I oversaw the development of software used by genomic sequencing labs and then proceeded into business and technology management positions spanning a portfolio of products in genomics, pathology and pre-clinical research.

Why Adaptive

While my career progressed in the U.S., back at home in India my mom developed ovarian cancer. We brought her to UCLA to get the best care. Despite many years of quality treatment, my mom passed away at the age of 59 – much too soon.

Being on the patient’s side of the cancer journey had a profound influence on my professional path. I discovered that my true passion is in improving patient care by launching products that I would recommend for myself, my family members, or my friends.

When I came across the opportunity to join Adaptive, I was impressed by how well-positioned the company was for success. We have incredible capabilities in sequencing, data analysis, bioinformatics, and computational biology. I saw the tremendous potential in having a positive impact on human beings with minimal residual disease (MRD) monitoring. I thought back to when my mom was sick, and wished we’d had a modern, more accurate MRD test available at that time for ovarian cancer.

The Future of Cancer Diagnostics

The diagnostics that we and others are developing measure the genome (an organism’s genes), proteome (proteins expressed by the genome) or the immune repertoire (an immune system’s T-cell receptor and B-cell receptors). We are attempting to fundamentally understand the underlying nature of disease and using that information to make the right therapy or treatment choices.

An increasing number of complex and innovative therapeutics, like immunotherapies, are generating incredible responses in patients. Measuring MRD is going to be very important as they continue to be implemented across the cancer continuum.

Further, the initiatives the US government has taken, including the most recent recommitment to the Cancer Moonshot by President Biden, bode well for cancer treatment in general. At Adaptive, we’re approaching cancer treatment and management from a variety of angles. Our MRD tests in blood or bone marrow are guiding blood cancer treatment and helping patients as these treatments become more effective. Our drug discovery partnership with Genentech is seeking to take cancer immunotherapy to the next level with novel cellular therapies.

“Patients first” is the barometer I have used every day since I was once on the other side with my mom. Too many of us have had family members impacted by this disease. I feel incredibly lucky that I get to do this work on a day-to-day basis. It is so much fun to be here and to be participating in this impactful journey that we as Adapters are taking together.