Andre Goy: Giving Patients Strength to Fight

Andre Goy, MD

Having a doctor tell you there’s a cure for your cancer is one thing. Having him inspire you with confidence to fight is another. That’s the gift Jerry Paragano, 79, received in 2010 when he went to Andre Goy, MD, MS, for a second opinion about his stage IV mantle cell lymphoma (MCL). Paragano had previously been told that he had 6 months to a year to live. Fortunately, he got a referral to Goy, an oncologist-hematologist and innovator at John Theurer Cancer Center (JTCC) in Hackensack, New Jersey, part of the Hackensack Meridian Health (HMH) network.

“When you just look at somebody and you trust them right away, that’s the kind of feeling I had,” Paragano recalled of that meeting. Goy put his hand on Paragano’s shoulder and told him not to worry. “I felt like I was on the ground and somebody lifted me right up,” Paragano said. Nine years later, he is still going strong and working at his tailoring and formal wear business in Hightstown, New Jersey.

“From day 1, when Dr Goy said, ‘We’ll fix this,’ I took it with that kind of attitude. He saved my life,” Paragano said.

From the Alpine community of Bonneville, France, where he grew up, Goy attended medical school and crossed the Atlantic to achieve a firm footing in the highest echelons of oncology and hematology practice. He is now chairman and director of JTCC and chief of the Division of Lymphoma at Hackensack University Medical Center (HUMC), as well as a prolific investigator who has played leading roles in the development of groundbreaking therapies in MCL (Timeline).

These include bortezomib (Velcade), the first proteasome inhibitor; lenalidomide (Revlimid), one of the first immunomodulatory drugs; ibrutinib (Imbruvica), the first Bruton tyrosine kinase (BTK) inhibitor; and, more recently, acalabrutinib (Calquence), a second-generation BTK inhibitor. He also participated in a pilot study for rituximab (Rituxan), the first anti-CD20 monoclonal antibody approved in blood cancers in the late 1990s, which has profoundly influenced the management of B-cell lymphoma and leukemia, as well as many autoimmune disorders.

At JTCC, Goy oversees clinical research, which has over 450 clinical trials ongoing. He initiated chimeric antigen receptor (CAR) T-cell therapy at JTCC more than 8 years ago in collaboration with the National Cancer Institute (NCI). He describes CAR T-cell therapy as “a game changer in both B-cell lymphomas and leukemias and likely beyond in the future.”

This winter, Goy will co-chair the 24th Annual International Congress on Hematologic Malignancies^® in Miami Beach, Florida, from February 27 to March 1, 2020. The conference, hosted by Physicians’ Education Resource^®, LLC, features a comprehensive workshop on CAR T-cell therapies in lymphoma, myeloma, and leukemia, followed by a full menu of presentations on the most important emerging trends and hot topics across hematologic malignancies. Jorge E. Cortes, MD, director of the Georgia Cancer Center at Augusta University, and Sagar Lonial, MD, FACP, chief medical officer of the Winship Cancer Institute of Emory University in Atlanta, are also co-chairing the event.

Recently, Goy sat down with OncologyLive^® for an interview about cutting-edge CAR T-cell therapy and other groundbreaking investigations, as well as his thoughts on general developments in oncology and hematology.

CAR T-Cell Therapies

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“We have performed well over 7500 BMTs [bone marrow transplants] and have been involved in CAR T-cell therapies since the early days together with the NCI and Steven Rosenberg team,” noted Goy, referring to the immunotherapy pioneer and 2013 Giants of Cancer Care^® award winner.

“Years from now, we will look back and think of CAR T cells and immunotherapy at large and as an inflection point in cancer care,” Goy said. “This new modality of therapy has shown extraordinary results using anti—CD-19 CAR T cells with an overall response rate [ORR] over 80% and a complete response [CR] rate over 50%. These results, now confirmed in the real-world setting, provide a new platform for patients who have failed multiple lines of therapy and who have practically no viable options.

“We have seen some patients with aggressive lymphoma who had an excess of 10 prior therapies and who achieved very durable responses after anti-CD19 CAR T-cell therapy. In addition, with longer follow-up, it seems that very few patients relapse after 6 to 8 months, suggesting that a significant proportion of these patients might potentially be cured,” Goy said.

“This being said, there are still true challenges and definitely opportunities to improve,” he continued. “Controlling or modulating toxicities, as well as preventing or managing early failures to CAR T-cell therapy, are the current focus of our research community.” Although different CAR T-cell constructs and products might have distinct toxicity profiles, ongoing trials are looking at ways to reduce toxicities through preemptive steroids, earlier use of tocilizumab (Actemra; a monoclonal antibody [mAb] anti—IL-6 receptor) or siltuximab (Sylvant; mAb anti–IL-6 receptor), and preclinical evidence suggests that a pharmacological “on-off switch” could be used to improve the safety of CAR T-cell therapy to control T cell expansion in vivo.

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Among these many new cell therapies in development are dual CAR T cells (2 targets, such as anti CD19/CD22), armored CAR T cells (engineered to secrete cytokines to further improve CAR T-cell efficacy in their microenvironment), and natural killer (NK) CAR T cells (potentially less toxic)², as well as “off-the-shelf” CAR T cells (“universal CAR T” that could greatly affect the field by not requiring customization of each therapy). In addition, combining CAR T cells with small molecules (ibrutinib, lenalidomide) or checkpoint inhibitors might enhance efficacy and/ or durability of these modified T cells.

Goy has led JTCC’s charge into CAR T-cell applications. One of the first CAR T-cell therapies his team worked with was axicabtagene ciloleucel (axi-cel; Yescarta), which was approved based on the pivotal ZUMA-1 trial in 2017 for adult patients with relapsed/ refractory (RR) large B-cell lymphoma after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Goy and fellow investigators at HMH continue to explore new CAR T-cell constructs in multiple myeloma, large cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia (CLL). Goy noted that additional trials are opening in Hodgkin lymphoma; acute myeloid leukemia; and, soon, solid tumors.

Not surprisingly, the impressive results seen with CAR T cells have created tremendous expectations. “Unfortunately, though, we do not have reliable ways to predict patients’ response, toxicity, or even durability of response at this point,” Goy said.

Tumor burden at baseline and the “inflammatory milieu” pre—CAR T-cell therapy have been associated with worse prognostic factors, supporting the rationale for bringing in CAR T cells earlier in ongoing trials. Impressive data from the American Society of Hematology (ASH) last year—based on measurable residual disease (MRD) quantified by cell-free DNA (cfDNA) assays—showed that MRD status at day 28 was highly predicative of a much better long-term outcome.

On the other hand, a significant number of patients who showed early partial response (PR) post CAR T cells have “converted” to durable CR. Although the importance of persistence of detectable CAR T cells over time is still debated, everyone agrees that both peak and area under the concentration time curve of CAR T-cell expansion post infusion highly correlate with response and outcome.

Mechanisms of resistance to CAR T-cell therapy are not fully elucidated and are likely multiple (eg, loss of antigen expression, immunosuppressive milieu, insufficient amplification or loss of CAR T cells, and T-cell exhaustion). “Naturally, combining with checkpoint inhibitors has been explored in order to enhance CAR T-cell efficacy,” Goy said.

The phase I portion of ZUMA-6 evaluated PD-L1 blockade with atezolizumab (Tecentriq) after axi-cel infusion in patients with refractory DLBCL. This demonstrated a manageable adverse events profile, significantly higher CAR T-cell expansion, and median CAR T-cell levels that, compared with results from ZUMA-1, remained higher 28 days longer than with axi-cel alone. The ORR in this small study (N = 10) was 90%, with 6 CRs (60%) and 3 PRs (30%). “Interestingly,” Goy said, “2 of 6 patients [33%] converted to CR at 6 and 9 months after achieving an initial PR.”³

The Relevance of New Findings

Multiple other therapies will be discussed during the 4-day International Congress on Hematologic Malignancies^®. Goy said that the diversity and depth of the agenda are emblematic of the tremendous pipeline in oncology and hematology. “We are incredibly fortunate to be practicing oncology at this time, even if medicine is facing serious and complex challenges, including in its rising costs as society,” he said.

These are just a few examples of radical shifts that are happening in medicine:

Biological Diversity

The growing awareness of the biological diversity of cancers, which can now be apprehended more easily, thanks to more accessible genomics, will allow for better patient stratification—ie, by definition practicing precise medicine, which will be covered in detail at the upcoming conference.

Biologic Combinations

The second main trend is a shift toward biological combinations away from chemotherapy. Although this has already been the case in CLL for several years, the trend is now penetrating other diseases, such as DLBCL, as shown recently by the group from The University of Texas MD Anderson Cancer Center in Houston at the 2019 International Conference on Malignant Lymphoma in Lugano, Switzerland.

In patients with the non—germinal center (GC) DLBCL subtype, a combination of rituximab, lenalidomide, and ibrutinib (R2-Ib) administered prior to chemotherapy demonstrated an 86% ORR and a 36% CR rate. A 98% response rate was achieved in patients who went on to receive standard chemotherapy.⁴ Although follow-up is still short, Goy called these findings highly impressive.

Another example is in MCL, in which multiple genetic abnormalities at baseline, such as p53 in particular, translate into very poor outcomes even after dose-intensive or highdose therapy followed by autologous stem cell transplantation. “Such patients seem to do really well with an ibrutinib plus rituximab [I-R] combination upfront followed by an abbreviated course of chemoimmunotherapy,” Goy said. “Testing for p53 overall is not done routinely enough, [whereas] other signatures, which will be reviewed in a very practical way during the Miami Beach conference, have already changed the management of acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma.”

MRD Monitoring

“MRD monitoring will undoubtedly become more prominent in the management of all cancers, I believe, while it is already penetrating the field of hematologic malignancies,” Goy said. “Relevant use of MRD and its impact will be reviewed at the conference across blood cancers, including: What is the optimal duration of therapy, including maintenance?

“This brings us to value-based and optimization of care: Given the mounting concerns about the complexity and costs of cancer care, several key issues will need to be addressed: How will we be able to rationalize medicine in order to improve outcomes and reduce cost along the way? What will be the best sequence of care and for how long?”

At the Forefront of Drug Development

The past 2 decades have seen astonishing advances in cancer treatment, particularly in MCL, and Goy has been at the forefront of this charge.

Goy’s journey in medicine began at the Université Joseph Fourier in Grenoble, France, where he received his initial medical training and continued with an internship and residency at Grenoble University Medical Center. He earned his medical degree in 1984 and decided to pursue oncology because he anticipated it would be everchanging and, thus, always engaging and challenging.

He earned a certificate and a master’s degree in immunology, as well as a master’s degree in experimental oncology. Simultaneously, he served as an oncology fellow at Albert Michallon University Medical Center of Grenoble.

Goy then attended the Pasteur Institute in Paris for a 2-year training, with research focused on tumor immunology (activation of NK cells and T cells using IL-2, referred to back then as lymphocytes activated killer [LAK] cells), before becoming an attending at Hospital Cochin, the second-largest university hospital in Paris.

Goy developed an interest in coming to the United States to study and pursued fellowships in oncology/hematology and lymphoma at Memorial Sloan Kettering (MSK) Cancer Center in New York, New York, which he completed in 1997. He was subsequently appointed as an attending at MSK’s Memorial Hospital before joining MD Anderson Cancer Center in 2001, where he witnessed many patients with relapsed MCL. This provided him with a strong motivation to explore novel therapies for these patients. He led studies in bortezomib that demonstrated significant gains over standard chemotherapies. These findings led to bortezomib’s approval in RR MCL in 2006. The pivotal PINNACLE trial results showed an ORR of 31% (median duration, 9.3 months) and a CR of 8% (median duration, 15.4 months).⁵

Two other game changers were lenalidomide⁶ and ibrutinib,⁷ both approved in RR MCL in 2013. Goy was involved firsthand in the development of these agents, which significantly changed the field of MCL.

Goy also participated in trials of the BTK inhibitor acalabrutinib, which was approved in the RR MCL setting in 2017. In the phase II ACE-LY-004 trial, patients who received oral acalabrutinib achieved an ORR of 80% (95% CI, 72%-87%) and a CR rate of 40% by independent review.⁸

Since Goy joined HUMC in 2005, he has seen over 600 patients with MCL. This has afforded him an opportunity to achieve a profound familiarity with the use of standard and novel therapies in this disease type.

The efforts to optimize the armamentarium continue. At JTCC, investigators have almost completed accrual for a study of lenalidomide plus R2-Ib in RR MCL that Goy said is showing “an incredibly high CR rate and durable response.”

“We have some patients who are well over 4 years out still in CR, in the RR setting, which is unheard of,” he said. This includes mostly elderly patients who would not have been candidates for allotransplantation, the only long-term option for such RR MCL patients.

“Finally, we have been involved early on in CAR T cells for patients with RR MCL through the ZUMA-2 study, and the results will be presented at the upcoming ASH meeting in December 2019. We can definitely see the light at the end of the tunnel in MCL,” Goy declared.

In addition, combining rituximab and lenalidomide (R²) with ibrutinib has been a success story for patients with RR DLBCL who are not candidates for stem cell transplantation. Goy noted that remissions in this setting have also been very durable, particularly in non-GC subtypes, showing once again that combinations of biological agents might supplant chemotherapy across numerous lymphoma subtypes.

Goy on Breaking the R-CHOP Ceiling

Not all investigations lead to success. Attempts to improve on the benchmark achieved by R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) in DLBCL have been disappointing, Goy said. First established in 1976, CHOP produced a 10-year overall survival in 10% of patients. It took almost 25 years to get to the next standard of care in 2000, when the addition of rituximab showed a true improvement over CHOP.

“Since many strategies were explored, from intensification to number of cycles [6 vs 8] or infusional therapy, all basically failed to show superiority to R-CHOP,” Goy said. “Nowadays, with standard R-CHOP, over 50% to 60% of patients do really well, and, in fact, patients who are event free at 24 months have similar survival to that of a general matched population.⁹

“On the other hand, most of the failures, which occur within the first 18 months of diagnosis, remain very difficult to salvage with current standard therapies, which provides a strong motivator to do better than R-CHOP alone,” Goy said.

“We’ve been looking at numerous strategies for improving on R-CHOP, and this has been truly a humbling experience,” Goy said. “All the R-CHOP-plus-X strategies so far have failed overall. Each one of these strategies had a promising rationale based on phase II data, though they failed to confirm benefit over standard R-CHOP in large randomized trials.

“A number of issues explain these negative and disappointing results—first, patient selection, which is confirmed by the unexpectedly good outcome seen in the control arms of several of such studies. For example, in several trials focusing on non-GC subtypes, which have worse outcomes, the 2-year progression-free survival was 78% to 80%, twice what had been reported in historical controls,” Goy said.

Other factors include issues related to the robustness of biomarkers, by immunohistochemistry or even molecular signatures, and delays in starting therapy (preenrollment phase to study biomarkers), among others. One of the most recent negative results was the ROBUST trial exploring R2-CHOP (lenalidomide plus R-CHOP) versus R-CHOP in non-GC DLBCL (20-gene signature, Lymph2X assay), which showed no difference,10 contradicting previous observations by several investigators that adding lenalidomide to R-CHOP mitigated the negative impact of a non-GC molecular subtype on outcome.

“The ECOG-ACRIN trial of R2-CHOP, which had a slightly different design, may be a bit more optimistic since it did show a 33% reduction in risk of progression or death versus R-CHOP [HR, 0.67; P = 0.03], although there was no difference in positron emission tomography—based CR or OS,” Goy said.¹¹

Pursuing Precision Medicine

DLBCL biological heterogeneity goes well beyond cell-of-origin GC versus non-GC. Although treatment failure with R-CHOP typically occurs early on and remains problematic, there is no significant difference in outcome between GC B-cell (GCB)—like DLBCL and non-GCB DLBCL after patients achieve a CR following 6 cycles of R-CHOP.

The improvement over standard R-CHOP will more likely result from the identification of high-risk molecular subtypes such as double hit lymphoma (DHL) and triple-hit lymphoma (THL)—by not just fluorescence in situ hybridization but also gene expression signatures—which might benefit from more intensive therapies well beyond etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R).

Exploring consolidation with CAR T cells in this setting is very appealing, as DHL and THL typically fail early and are difficult to salvage, Goy said. “Obviously, the implications of the molecular complexity of DLBCL as a disease are still being elucidated but will help refine patients into subsets that are molecularly relevant and where targeted therapy combinations could have a more reliable impact,” he said. “Finally, cfDNA and MRD testing will become part of what we do in the future, supporting the emerging concept of ‘molecular CR in DLBCL.’ ”

The patients who are MRD-negative based on cfDNA [testing] after 2 cycles of R-CHOP do extremely well regardless of their initial presentation, Goy said. In addition, the field will likely evolve toward strategies of “immunoconsolidation” post induction, which might help prevent relapse.

At JTCC, Goy and fellow investigators have pursued multiple avenues for improved stratification of patients with lymphomas via the use of biomarkers. “In MCL, if patients carry both TP53 abnormality and ATM deletion at baseline, the median overall survival is less than 1 year even after high-dose/dose-intensive therapy. This has provided a rationale for bypassing chemotherapy, particularly in MCL, as shown by Michael Wang at MD Anderson,¹²” Goy said. “We start with R² plus ibrutinib or ibrutinib/rituximab and bring them into remission—hopefully, MRD negative— and then patients receive consolidation using shorter chemotherapy.”

It is still early, but this approach appears very promising. Other ongoing studies are looking at fully chemotherapy-free options in MCL, an appealing concept given the median age of patients at diagnosis: mid-to-late 60s.

At JTCC, Goy has fostered a patient-centric approach that has given life and dynamism to the cancer program there and inspires patients to believe in their ability to fight cancer, said Sharon Lee Parker, a 17-year survivor of metastatic follicular variant papillary thyroid cancer and nodular sclerosing Hodgkin lymphoma. She was referred to Goy during his days at MD Anderson. Like Paragano, she found strength in Goy’s confidence that he could help her beat her cancers.

“His charm, his sincerity, and his brilliance were so apparent to me. He seemed so genuinely passionate about finding the cures and figuring out how to improve the quality of life for patients,” Parker said. She later came to HUMC, where she became a board member and patient ambassador, bringing her skills from a longtime career in the hospitality industry to bear on improving the patient experience. Goy would refer his patients to her for encouragement and support.

Where Everybody Has a Letter C

One of Goy’s achievements in this respect is JTCC’s annual Celebrating Life and Liberty event for survivors of cancer and their families. Launched in 2008, the event has grown spectacularly from 700 attendees to thousands and is now held at MetLife Stadium in East Rutherford, New Jersey.

The event has expanded to include patients from HUMC and its many affiliates. Goy anticipates that as many as 7000 will attend this year’s celebration. “It was a simple idea that resonated very well with our patient community, which made it a true success,” he said.

“This event allows patients to cross-pollinate and share their stories, challenges, and journeys. Every patient with cancer walks through life thinking they are ‘outsiders with a big C on their back.’ At the event, everyone has one. There’s lightness and happiness in the air.”

Goy is also the founding chair of the oncology department at the newly formed Hackensack Meridian School of Medicine at Seton Hall, which enrolled its second class of students this summer (from a pool of over 5000 applicants in 2019). The school provides an innovative 3-year path to residency designed to reduce the cost of a medical education. “We are thankful to have built a large network of 18 hospitals, with an academic medical center, and a Center for Discovery and Innovation at the ex-Roche headquarters in Nutley, New Jersey. This provides you with opportunities to accelerate discovery but also provides us with the duty to prepare the physicians of tomorrow,” Goy said. “It is a once-in-a-lifetime opportunity to build a medical school from scratch.”

Not surprisingly, teaching the physicians of tomorrow comes with many challenges. “Finding the right balance between science and humanity, being a great clinician but keeping interest in research, embracing innovation but being mindful of costs and being responsible… These challenges are in fact a tremendous opportunity as they will help us embrace the upcoming transformational changes we face in health and healthcare delivery,” Goy said.

“At the school of medicine, we pair 4 students from the first day on with families in their homes, so they can get engaged in real-world ecosystems; focus on prevention and education; and, hopefully, further develop empathy, a fundamental tool to practice the art of medicine,” he said.

Much has been said about the arduousness of the oncologist’s training and life, the long hours, the time spent filling in the electronic health records (EHRs), and the stress all that places on a doctor’s psyche. For all those reasons, the shortage of oncologists has been predicted to grow worse.

Goy sees things differently. The steady pace of advances in treatment and the ongoing reinvention of cancer medicine are lures for bright young minds, he said: “I think oncology is the most exciting medicine in our lifetime. I’m not worried about physicians not becoming inclined toward cancer care. With the palpable pace of innovation, the sense of game-changing therapies we have, physicians will want to go into this.”

Amid the rapid changes in oncology and medicine in general, Goy worries that the “elegant art of doctoring” is being displaced or disrupted by technology, from the growing EHR requirements to the constant urge to check an electronic device for confirmation. The burden imposed on providers to capture data and the increasing compliance requirements, frequently just to process documentation, have drastically reduced face-to-face patient—physician time and put pressure on physician time. Navigators have become the “next big thing” in part because patients are “lost between multiple providers,” who spend precious time documenting their “piece of the puzzle,” Goy said.

“Undeniably, technological advances have and will benefit clinical medicine, but we are currently at a crossroads, and it is time to tip the balance back toward our patients while making the most of the amazing technology now at our fingertips,” he said. “I am convinced that a key solution to current healthcare issues is to promote the art of clinical science, a foundation for robust medicine in the future.

“Medicine is really understanding and listening to a patient. I had a professor early on in training in France who used to always refer to William Osler’s famous quote: ‘Listen to your patient. He’s telling you the diagnosis.’ It’s very true. Having the ability to be a clinician is being an observer, including understanding the dynamics as you walk in a room. This is very useful as it will help you influence the context when needed to help your patient have the best outcome. Part of this is truly about bedside manners and empathy. Patients are first and foremost human beings. I’m totally convinced this affects the outcome.

“I am very optimistic that the obvious benefit of great clinical practice will win,” Goy said. “Technology and smart phones are tools to give you back time to practice medicine.”

“It is rather impressive to see that there are over 1000 individual cell therapies in the pipeline, more than half being variants of CAR T cells,” Goy said.¹ “This impressive portfolio of cell therapies is a testimony to our collective conviction that these therapies will continue to revolutionize the field.”

“First, I want to tell you how proud I am about JTCC and all of my colleagues who have truly made us a premier oncology program in just over 2 decades,” Goy said. “I could not be more thankful to lead JTCC, the largest oncology program in New Jersey by far, which is at the forefront of drug development and innovation (Table).

References

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8. Acalabrutinib [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210259s000lbl.pdf. Accessed September 4, 2019.
9. Goy A. Succeeding in breaking the R-CHOP ceiling in DLBCL: learning from negative trials. J Clin Oncol. 2017;35(31):3519-3522. doi: 10.1200/JCO.2017.74.7360.
10. Vitolo U, Witzig TE, Gascoyne RD, et al; ROBUST study investigators. ROBUST: first report of phase III randomized study of lenalidomide/R‐CHOP (R2‐CHOP) vs placebo/R‐CHOP in previously untreated ABC‐type diffuse large B‐cell lymphoma. Hematol Oncol. 2019;37(S2)36-37. Abstract 005. doi: 10.1002/hon.5_2629.
11. Nowakowski GS, Hong F, Scott DW, et al. Addition of lenalidomide to R-CHOP (R2CHOP) improves outcomes in newly diagnosed diffuse large B-cell lymphoma (DLBCL): first report of ECOG-ACRIN1412 a randomized phase 2 US Intergroup study of R2CHOP vs R-CHOP. Hematol Oncol. 2019;37(suppl 2). doi: 10.1002/hon.6_2629.
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