How Antibody Drug Conjugates—and Chemotherapy Shortages—Are Affecting Patients With Bladder Cancer

At an evening dedicated to innovation in cancer care, Emory’s Jacqueline T. Brown, MD, assistant professor at the Winship Cancer Institute, explained how her area of specialty—genitourinary malignancies—has become a poster child for the extremes of care delivery.

Brown

Brown spoke on “Antibody-Drug Conjugates in Advanced Urothelial Carcinoma,” at the July 25, 2023, session of the Institute for Value-Based Medicine®, presented by Winship with The American Journal of Managed Care®. Her main talk covered how the rise of this drug class, and the approval of 2 ADCs in particular, have elevated the standard of care in the sixth most common cancer.

But at the other end of the spectrum, the shortages of cisplatin and carboplatin, 2 “cornerstone” chemotherapies, have created tough decisions for doctors and patients alike—and brought issues of health equity into sharp focus.

The Magic Bullet

Brown started with German scientist Paul Ehrlich, whose work led to chemotherapy; he won the 1908 Nobel Prize for Medicine and first conceived the idea of the “magic bullet,” an agent that would take out a pathogen without disturbing the cells around it.¹

“We know that chemotherapy is not a magic bullet,” Brown said. “The toxicity from traditional chemotherapy is attributed to nonspecific drug exposure to these off target tissues. And when I'm talking to patients, and I'm explaining to them what they can expect from traditional chemotherapy, I say, ‘These are drugs that kill cells that divide quickly, and so that ends up resulting in our toxicities like cytopenias, and [gastrointestinal] upset and hair and nail changes.”

“So, the Holy Grail would really be to create a drug that is able to kill malignant cells and leave normal cells unharmed,” she said. “That's the real magic bullet.”

ADCs come much closer to that concept, Brown explained, with a 3-part structure that features a monoclonal antibody specific to an antigen expressed on target tissue, specifically cell surfaces, but not on normal tissue. “And when the monoclonal antibody binds to that target, it then needs to be able to be internalized and transported within the cell,” she said.

The ADC structure features a covalent linker, either cleavable or non-cleavable, which guarantees proper delivery of the “cytotoxic payload” at just the right time, to avoid affecting non-target tissues. The payload kills cancer cells and can come in 3 different types: DNA damagers, tubulin-binding agents, or topoisomerase-1 inhibitors. In some cases, she explained, the payload can be taken up by nearby cells in what is called the “bystander effect.”

Brown presented diagrams of 14 ADCs approved starting in 2000 across multiple disease types, as well as the types under development; she noted the pair approved in bladder cancer, which are enfortumab vedotin (EV) and sacituzumab govitecan (SG).^2,3

A Deadly Disease

“What is metastatic urothelial carcinoma?” Brown asked, “Why this is a disease that matters?”

Urothelial carcinoma can start anywhere in the urinary tract, she said, but 90% of cases start in the bladder, with 10% from the ureter, uretha, or renal pelvis. When the cancer spreads beyond the bladder, there is a median survival of 2 years in clinical trials; Brown said in the real-world population, survival is likely shorter.

A 2018 study shows that only 42% of patients ever receive first-line therapy.⁴ “That's a pretty high attrition rate in a pretty aggressive disease. Of those only 27% received standard of care, cisplatin chemotherapy,” she said, noting there were likely many reasons for this, from cisplatin ineligibility to pre-existing neuropathy. Only 15% to 20% received second-line therapy and “a measly 6% received third-line therapy.”

“If we can have a take home from this slide, this is an aggressive disease and this is a deadly disease,” Brown said. “The key to actually moving the needle on survival is not only having good drugs, but also moving them to early lines of therapy so that your patients actually have the opportunity to benefit from those drugs.”

Since Brown became an independent practicing oncologist in 2021, change has been swift in urothelial carcinoma. In 2016, platinum-based chemotherapy was the only option, but since that time approvals of both targeted agents and now ADCs have arrived. In April 2023, FDA approved EV plus pembrolizumab for the treatment of cisplatin-ineligible first-line metastatic urothelial carcinoma,⁵ based on the EV-103 trial (NCT03288545).⁶

Brown elabaorated on EV. “This is an antibody drug conjugate targeted against Nectin-4,” a surface marker involved in cell proliferation and migration. “It's expressed in multiple cancers, but maybe none as highly as urothelial cancer—it’s 80% to 90% of bladder cancer cells. The payload in this drug is MMAE (monomethyl auristatin E), which is a very traditional microtubule inhibitor involved in multiple other drugs in this space.”

She reviewed data from the phase 3 EV-301 trial (NCT03474107) that led to the drug’s approval. Median overall survival (OS) was 12.88 months for EV compared with 8.97 months for chemotherapy; response rate for EV was 40.6% vs 17.9% for chemotherapy in a heavily pretreated population.⁷

“I think a really key concept with antibody drug conjugates is this idea of that you can have 2 different types of toxicity,” Brown said. “You can have on-target toxicity because the antigen is expressed in non-tumor tissue, and then you can also have off-target toxicity.”

If patients stay on the drug long enough, she said, they will experience peripheral neuropathy; about a third of patients are affected. Other common adverse effects are gastrointestinal effects and cytopenias.

Moving EV with pembrolizumab into first-line treatment for cisplatin-ineligible disease was practice changing, Brown said. In the trial, “The objective response rate in this population was 64.5%. For people aren't as aware of what that means, 64.5% of patients had shrinkage of their tumor by more than 30%. That's something that would have been unheard of before. And when we compare it to cisplatin from what we know, we're generally talking about 40% to 50%. That number was really amazing to everybody.”

What’s more, she said, there were confirmed complete and partial responses in patients whose disease did not express Nectin-4, which she called, “hypothesis generating.” Results from another trial, EV-302 (NCT04223856), in cisplatin-eligible patients,⁸ will show whether this chemotherapy has been “dethroned as king in first line urothelial carcinoma.”

The TROPHY-U-01 trial (NCT03547973)led to approval for SG,⁹ which targets TROP2; this drug is a topoisomerase-1 inhibitor with a payload of SN-38, which Brown said, “causes DNA single strand breaks and ultimately death of the tumor cell.”

In heavily pretreated patients, the response rate was 27%, and 77% had some tumor shrinkage, leading to accelerated approval in the third-line setting. Brown described toxicities for SG as “more straightforward,” than EV; it causes severe cytopenias, neutropenic fever, and diarrhea; and granulocyte-colony stimulating factor is often required.

A New Paradigm?

The use of EV with pembrolizumab could represent “a new paradigm,” Brown said. She reviewed other combinations in the pipeline: another cohort of the TROPHY-U-01 study involves ADC with immunotherapy. The DESTINY-PanTumor02 results (NCT04482309), presented this year at the American Society of Clinical Oncology, looked at the ADC trastuzumab deruxtecan across multiple cancer types,¹⁰ including bladder cancer, with a 39% objective response overall. A phase 1b study will examine this ADC with the PD-1 inhibitor nivolumab in metastatic urothelial cancer with HER2 expression. Disitamab vedotin plus toripalimab in treatment-naïve disease produced an ORR of 73% in a small phase 1/2 study. “Again, unheard of numbers in urothelial carcinoma—so this is very encouraging.”

But while the promise of ADC combinations become the standard of care seems closer, it’s not yet here. And for now, if a patient is eligible for cisplatin, that’s still the standard—except it’s become hard to find. “Most people in this room are probably relatively aware,” of the shortages. “You can imagine the really dire impacts this has had on managing this disease across the country.”

Brown shared the well-known story of the FDA’s need to shut a factory in India that made most of the country’s carboplatin for quality control issues, which triggered the current supply chain nightmare. First carboplatin, then cisplatin ran short, as patients taking carboplatin were switched to a different drug.

“ASCO issued guidelines on how to navigate these drug shortages,” Brown said. “In short, the main take home messages from this are, use other things whenever you can, and in palliative patients if you can spread out the interval of treatment with these drugs, please do so.”

Brown said when she moved a patient’s carboplatin from every 3 weeks to every 4 weeks, the patient asked, “Are you rationing care? And I said, ‘I guess that I am,’ in an effort to be honest with him.”

An Uncomfortable Conversation

Per ASCO guidelines, in urothelial cancer, she said, if cisplatin is not available, the alternative would be to use EV plus pembrolizumab, or pembrolizumab alone. And for cisplatin-eligible patients, Brown reminded the audience, the combination is not yet FDA approved, and pembrolizumab alone “would be considered substandard care in 2023. If you are eligible for chemo, you should get chemo.”

“Of course, the elephant in the room is the astronomical cost differences between these drugs,” she continued. “I believe in these drugs; I believe in the data that I just presented to you, I use them regularly. And I know the very real impact they have on our patients. But also remember that one of the pillars of medical ethics is justice. And namely, that is the equitable and fair distribution of our health resources.

“I have colleagues across the country in various regions who have not been able to give even the drugs I have on the screen to their patients, let alone our colleagues internationally, who may show up to a big meeting, and beyond inspired by the data being presented, but it has really no impact on their Monday morning treatment, because they just don't have those drugs to give people. And I think it's our collective responsibility to create a health system that is sustainable.

“I often think of myself as part of the problem, I think about this with some frequency. And so, I think we have to agree to continue this conversation as uncomfortable as it may be.”

Brown noted that the FDA recently addressed the shortage by allowing imports of cisplatin from China.¹¹ But the question of when the next shortage will arise goes on, she said.

“I want to conclude with a couple thoughts. One is which to remind you that antibody drug conjugates have absolutely revolutionized the treatment of urothelial carcinoma. The needle for survival is moving in this disease. And it's because of these drugs period. But critical drug shortages have had really big impacts, requiring implementation and mitigation strategies, reliance on more expensive alternatives, and in some cases, even rationing care.

“And lastly,” she said, “with great power comes great responsibility. But we have to remember that as technology advances, we have to control costs and avoid deepening inequities in access and outcomes.”

References

1. Paul Ehrlich. Science History Institute. Accessed August 4, 2023. https://bit.ly/3Opao2q
2. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. FDA. July 9, 2021. Accessed August 4, 2023. https://bit.ly/3QlzBgY
3. FDA grants accelerated approval for Sacituzumab govitecan in advanced urothelial cancer. FDA. April 13, 2021. Accessed August 4, 2023. https://bit.ly/3DJKSjO
4. Galsky MD, Kumar Pal S, Lin SW, et al. Real-World Effectiveness of Chemotherapy in Elderly Patients With Metastatic Bladder Cancer in the United States. Bladder Cancer. 2018;4(2):227-238. doi: 10.3233/BLC-170149
5. FDA grants accelerated approval for enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. April 4, 2023. Accessed August 4, 2023. https://bit.ly/456fgjU
6. O’Donnell PH, Milowsky MI, Petrylak DP, et al. Enfortumab vedotin with or without pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial cancer. J Clin Oncol. Published online June 27, 2023. doi: 10.1200/JCO.22.02887
7. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135. . doi: 10.1056/NEJMoa2035807
8. Van der Heijden MS, Gupta S, Galsky MD, et al. Study EV-302: A two-arm, open-label, randomized controlled phase 3 study of enfortumab vedotin in combination with pembrolizumab versus chemotherapy in previously untreated advanced urothelial carcinoma (aUC) (trial in progress). J Clin Oncol. 2022;40(suppl 6):abstr TPS589. doi:10.1200/JCO.2022.40.6_suppl.TPS589
9. Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: a phase 2 open-label study of Sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39(22):2474-2485. doi: 10.1200/JCO.20.03489
10. Meric-Bernstam F, Makker V, Oaknin A. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol. 2023;41 (suppl 17): abstr LBA3000: doi: 10.1200/JCO.2023.41.17_suppl.LBA3000
11. FDA to allow import of oncology drug amid nationwide shortage. News release. American Hospital Association. June 2, 2023. Accessed August 4, 2023. https://bit.ly/3s5D0Go