ASCO 2019: Chemotherapy, Antibody Drug Conjugates, and Radiation with or without Anti-PD1/Anti-PD-L1

Chicago, IL (UroToday.com) In this series of presentations, Dr. Petros Grivas and colleagues walk through the conceptual framework for therapeutic development beyond anti-PD1/PD-L1 therapy for urothelial cancer. Their talks are synthesized into a paper that was published in the American Society of Clinical Oncology Educational Book in January of 2019. While these presentations were heavy on details, the overarching themes and points are synthesized below.

In this presentation, Alexandra Drakaki, MD, focused on chemotherapy options, antibody drug conjugates (ADCs) and radiation therapy with or without PD-(L)1 targeting.

Chemotherapy:

Chemotherapy has a 40-year history in the treatment of advanced urothelial carcinoma. More importantly, while the attention has turned to immunotherapy (IO), it should be clear that chemotherapy is an important tool in this disease, remaining the first line treatment option in all guidelines. It has yet to be supplanted in the first line cis-eligible setting.

While the discussion has always been to replace chemotherapy with IO, primarily due to older notions that chemotherapy directly killed tumor cells and was immunosuppressive, newer data suggest that chemotherapy has pleiotropic effects, including stimulation of the innate and adaptive immune system via cell death and antigen release and alteration in the tumor microenvironment. Hence, this has naturally raised the option of combination therapy with synergistic effects. This combination has been found to be effective in other malignancies, including breast, NSCLC, and SCLC. So, there is rationale and evidence for its efficacy — it just needs to be tested in bladder cancer.

Below is a slide summarizing the first line chemotherapy / ICI combination studies:

The last study (CALGB 90601) is being reported here at ASCO 2019.

However, as these trials develop, she reminds us to ask the right questions:

Are we overtreating our patients? Are we doing more harm than good?
Are we cost effective?
Does everyone need the “treatment all at once” approach?
Can we sequence our current treatments instead?

Two studies may provide some more information on the question of sequencing:

GU14-182 (PI Matt Galsky) – pembrolizumab as maintenance therapy after initial chemotherapy in metastatic urothelial carcinoma (mUC)
JAVELIN Bladder 100 (PI Tom Powles) – avelumab in patients with locally advanced or metastatic UC

Dr. Drakaki notes that in the neoadjuvant setting, the PURE-01 and ABACUS trials demonstrating promising efficacy comparable to neoadjuvant chemotherapy:

Already, there is a push to look at the combination of chemotherapy with IO’s in this disease space, to help increase the response rates – and help prevent mUC altogether. Three studies she highlighted are below:

The last, SWOG S1314, was presented at ASCO 2019.

Three other studies (NIAGARA, CA017-078, and KEYNOTE 866) take a combined neoadjuvant/adjuvant approach, as they continue adjuvant IO following radical cystectomy.

Antibody-Drug Conjugates:

Antibody-drug conjugates are the use of monoclonal antibodies specific for the tumor conjugated to a cytotoxic agent (carrier model), seen below:

This, in theory, allows for selective targeting of cancer cells vs. normal tissue.

The primary agent in this space is Enfortumab Vedontin (EV), which has been granted breakthrough status by the FDA for bladder cancer. It delivers a microtubule-disrupting agent to tumors expressing nectin-4, which is a cell adhesion molecule overexpressed in UC cells (93% in mUC specimens). Rosenberg et al. (ASCO 2018) reported phase 1 study results of monotherapy in mUC patients, and found a 4% CR rate, 37% PR rate, 41% ORR, and a 71% DCR! The following are EV ongoing trials:

EV103 – phase 1 of EV with pembro and/or platinum-based chemotherapy.
EV203 – phase 2 of EV in patients with prior ICI and platinum-based chemotherapy (D. Petrylak is presenting this later at this meeting).
EV301 – phase 3 of EV vs. 2^nd line standard of care in patients who have failed platinum based chemotherapy and ICI.

There are also emerging ADCs targeting HER-2 and TROP-2.

Radiation Therapy:

Lastly, she introduced the concept of adding radiation therapy as an adjunct to ICI/IOs. The theory is that there may be an abscopal effect – and radiation may cause a release of antigens, dendritic cell activation, induction of systemic immune response.

She was relatively brief in her discussion of this session, and just highlighted the studies ongoing in the nonmuscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC) and metastatic urothelial carcinoma (mUC) settings:

Ultimately, while all of these combinations are promising, the key is to find balance.

Presented by: Alexandra Drakaki, MD, Medicine, Hematology Medicine, Medical Oncology, Internal Medicine, UCLA Medical Center, Santa Monica, CA

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

References:

Grivas P, Drakaki A, Friedlander TW, Sonpavde G. Conceptual Framework for Therapeutic Development Beyond Anti-PD-1/PD-L1 in Urothelial Cancer. Am Soc Clin Oncol Educ Book. 2019 Jan;39:284-300. doi: 10.1200/EDBK_237449. Epub 2019 May 17. PMID: 31099684

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