Hans Hammers, MD, PhD – Driving Immunotherapy Combinations Into the Modern Age of Kidney Cancer Care

Hans Hammers, MD, PhD, is a distinguished professor in the Department of Internal Medicine at UT Southwestern Medical Center. He also serves as a member of the Division of Hematology and Oncology, is a co-leader for clinical research and immunotherapy in the Kidney Cancer Research Program, and is a co-leader of the Experimental Therapeutics Program. Dr. Hammers’ primary research focus centers on the development of innovative immunotherapies for kidney cancer.

In an exclusive interview with GU Oncology Now, Dr. Hammers provides insight into his journey as a leading expert in kidney cancer research and immunotherapy. He discusses the pivotal clinical trials he has led that have significantly impacted outcomes for patients with kidney cancer and shares his perspectives on the future of novel immunotherapies and targeted therapies for kidney cancer.

To begin, could you share your background and explain why you chose to specialize in kidney cancer? What motivated you to enter this field and become a prominent figure in kidney cancer research and immunotherapy?

Dr. Hammers: My journey into kidney cancer research was influenced by a mix of serendipity and personal interest. Back when I completed medical school, I was captivated by Gina Kolata’s New York Times article on blood vessel inhibition and its potential impact on tumor growth. This concept of controlling tumors by targeting blood vessels fascinated me. As I pursued further medical training, I gravitated toward faculty members who were engaged in angiogenesis research. At that time, kidney cancer emerged as a prominent focus in this area, led by experts like Roberto Pili at the Johns Hopkins Hospital. A position opened up for me at Johns Hopkins, and that is how it all started. That position led to my immersion in kidney cancer research and its intersection with immunotherapy.

It was a very interesting time, not only from the perspective of blood vessel inhibition, but, in particular, the evaluation of immune checkpoint inhibitors in kidney cancer. The first phase 1 studies were being conducted, and some of the initial work was done at Johns Hopkins. I had the privilege of being a witness and part of it at the time.

Your journey was guided by a combination of fortuitous timing and the emergence of promising research. Could you provide more context regarding the timeline of your involvement in kidney cancer research and immunotherapy?

Dr. Hammers: I joined the faculty at Johns Hopkins in 2009. Prior to that, I worked toward earning a medical degree in Germany and then moved to the United States in 2000 due to personal circumstances. During my time in the United States, I began working for a biotech company in Bethesda, Maryland, EntreMed (now CASI Pharmaceuticals), which was focusing on angiostatin/endostatin molecules. This opportunity aligned with my research interests and clinical aspirations.

I worked in the drug discovery group at EntreMed for 1 year. Then it became clear that I could combine some of my research interests with clinical work and training. I was offered a position at one of the teaching hospitals at Johns Hopkins, and that is how my career started. I did my training, residency, and internship there through 2005, and then I was fortunate to be selected as one of the fellows to stay on in 2009, which was right around the time immunotherapies started to take off. From 2009 to 2016, clinical trials involving nivolumab monotherapy, and later the initial CheckMate 016 trial of nivolumab plus ipilimumab and the pivotal Checkmate 214 trial, took place. The latter trial is perhaps, to this day, the most potent immunotherapy available in kidney cancer.

Could you elaborate on your transition to UT Southwestern and the significance of your work there?

Dr. Hammers: My tenure at Johns Hopkins lasted until 2016, when I connected with Dr. Brugarolas, who was instrumental in establishing the kidney cancer program at UT Southwestern. This transition was motivated by my desire to work within a more comprehensive kidney cancer program. UT Southwestern’s emphasis on kidney cancer and its diverse research landscape greatly appealed to me. This institution allowed me to further contribute to kidney cancer research and advance my work.

You have been involved in some groundbreaking clinical trials, especially those related to nivolumab. Could you speak about your participation in those early immunotherapy trials for kidney cancer and your insights on their significance?

Dr. Hammers: During the late 2000s, I engaged in phase 1 clinical trials that explored the application of immunotherapy to kidney cancer. These trials evaluated the potential of immunotherapy agents like nivolumab in controlling tumor growth. Notably, I participated in studies such as CheckMate 009 and CheckMate 010, which assessed the effects of nivolumab monotherapy. My involvement in CheckMate 025, which assessed second- and third-line nivolumab monotherapy, led to the US Food and Drug Administration approval of nivolumab for pretreated patients. CheckMate 016 was also critical in establishing the safety and effectiveness of nivolumab in combination with ipilimumab. This outcome contributed to the design of CheckMate 214, a phase 3 trial that demonstrated the superiority of the nivolumab-plus-ipilimumab combination compared with sunitinib in advanced kidney cancer in 2018. Results of CheckMate 214 were published in the New England Journal of Medicine, and those results still guide care today.

Before we dive into your ongoing work, I would like to touch on something from the 2023 ASCO Annual Meeting that caught my attention—a discussion related to lenvatinib and your experiences with patients. Could you briefly share your insights on this? While lenvatinib is a targeted therapy, it differs from your work in the immunotherapy realm. Nevertheless, it is held in high regard, particularly in combination therapies for advanced disease. I am interested in learning about patient responses and your overall perspective on the treatment.

Dr. Hammers: To provide context, there are 2 main frontline therapies. One involves pure immunotherapy using PD-1/CTLA-4, which intensifies the immunotherapy approach. However, this treatment comes with an elevated risk of autoimmune side effects, requiring prednisone in about 30% of cases. The benefit is the remarkable, enduring responses – it is arguably the most promising regimen when long term outcome and benefit is considered. The caveat is that around 20% of patients progress right through to this immunotherapy.

The second approach combines PD-1/tyrosine kinase inhibitors (TKIs), creating a lighter immunotherapy option. It omits CTLA-4 but includes a vascular endothelial growth factor receptor-TKI, targeting blood vessels. Importantly, it is evident that these 2 therapeutic classes do not synergize. They combine their effects. There are 3 TKIs in this category: axitinib, cabozantinib, and lenvatinib. They progressively enhance in potency, with cabozantinib and lenvatinib being more potent than axitinib when combined with immunotherapy.

In this sphere, lenvatinib boasts the highest response rate at around 70%. Its progression-free survival (PFS) spans 2 years compared with 15 to 16 months in other PD-1/TKI combinations. For patients facing high-volume or highly symptomatic disease, where swift disease control is vital, I tend to favor lenvatinib/pembrolizumab. It presents fewer liver-related side effects than its counterparts, though blood pressure management might be a bit more intricate. In my experience, this regimen has yielded positive results, though managing TKI toxicity requires careful consideration. For patients who need a robust response and minimal progression, lenvatinib/pembrolizumab stands out to me.

Is your preference for lenvatinib/pembrolizumab rooted in data or personal experience?

Dr. Hammers: Both. We do have data to reference. While cross-trial comparisons come with caveats, lenvatinib combination trials exhibit the highest response and complete response rates, along with superior PFS, compared with reasonably comparable control groups. My experience aligns with these pivotal trial findings, leading to my preference.

Moving forward, could you detail your ongoing research efforts? What is happening in your lab regarding novel immunotherapies or other targeted approaches for kidney cancer? Are there specific preclinical or late-stage clinical trials about which you are particularly excited?

Dr. Hammers: Our clinical research ventures focus on fresh combinations and novel agents. I am part of the Department of Defense-supported Clinical Trials Consortium, collaborating with esteemed sites like MD Anderson, Michigan, Duke, Vanderbilt, and Beth Israel. Together, we are working on innovative trials exploring new combinations, drugs, and triplet therapies. The goal is to improve the long-term outcomes beyond initial disease control. While some trials like COSMIC-313 have faced setbacks, others, like LITESPARK-012, which is analyzing lenvatinib with pembrolizumab and a CTLA-4 inhibitor, show promise. The field is teeming with new targets and biotech-developed agents that could reshape kidney cancer treatments. I am fortunate to contribute to trial design and accrual.

On the lab front, I collaborate extensively with a UT Southwestern colleague. We are building on my background in preclinical drug development, combining small molecules with proinflammatory drugs. Similar to approved radioactive therapies for prostate cancer, we are designing pro drugs that release highly proinflammatory molecules like TLR7 and TLR9 upon cellular entry. These molecules are tailored to the neovasculature of kidney cancer, presenting exciting avenues for treatment. These efforts are being pursued in partnership with a small company we established, with patents in place.

We have covered a lot of ground regarding the future of kidney cancer treatment. As you mentioned, the landscape is poised for significant advancements, both from upcoming data readouts and the progression of lab research into practical treatments in the years ahead. Is there anything else you would like to share?

Dr. Hammers: It is crucial to highlight the significance of hypoxia-inducible factor-2α (HIF2α) inhibitors. These inhibitors are on the horizon and hold great promise. Phase 3 trials are in the pipeline, with some expected to report results soon and others further down the line. It is worth noting that the discovery of HIF2α as a unique target originated here at UT Southwestern, and its development was initiated by the spinoff company Peloton, ultimately acquired by Merck.

HIF2α is truly remarkable. In the realm of clear cell kidney cancer, it is poised to be the third pillar. Although it might not be universally effective, it boasts exceptional tolerability as a targeted therapy, which is rare. The absence of severe side effects coupled with the potential for long-term use makes it almost a holy grail in this field. Particularly for patients with von Hippel-Lindau (VHL) disease, it is a game-changer, delivering high response rates, tumor control, and extended treatment durations measured in years. In the realm of VHL-dependent biology, it is a transformative breakthrough that is set to profoundly impact the treatment of clear cell kidney cancer.