His first point, I thought was very important. Why do we give combination therapies?
- Synergy – where 1 + 1 > 2 – greater than their parts
- Additive – where 1 + 1 = 2
- Independent drug action - where 1 + 1 = 1*
* response of any individual patient to the combination is the patient’s response to the more effective drug for them
This last interaction is depicted in the picture below:
Where if you take a large population of patients and give them combination therapy, there may be some patients that have synergistic responses – but there may be populations that have responses to one or the other. Hence, in a large enough cohort, combination therapy will look to be more effective than monotherapy.
Therefore the approach to combination therapy can be:
1) Combine drugs with single-agent activity
2) Dissect and overcome mechanisms of resistance
The latter is the rationale for chemotherapy and immuno-oncology (IO) combination therapies. But it should be noted that different chemotherapy backbones may act differently – ie cisplatin and carboplatin (while both platinum-based and similar mechanisms of action), they may have different outcomes when combined with the same IO.
Combining IO’s with antibody-drug conjugates (such as enfortumab vedotin or RC48). Preliminary data presented as ASCO 2021 suggested this combination has promise.
Perhaps this is because enfortumab vedotin (EV) generates immunogenic cell death.
FGFR3 inhibitors and PD-1/PD-L1 blockade is another combination being assessed. These include erdafitinib and rogaratinib. Data presented as ESMO 2020 and ASCO 2021 suggest response for these combinations as well.
On the other hand, hitting the checkpoint blockade harder with the combination of CTLA-4 and PD-1/PD-L1 blockade has been another approach. Combinations have generally had better responses (though also with more toxicity) than single-agent therapy. Examples include ipi/nivo and durva/treme.
In a separate analysis, Wang et al.1 completed an unbiased discovery of gene signatures associated with sensitivity/resistance. They found 3 sets of signatures. The adaptive immune response signature was associated with a better response to checkpoint inhibitors, while stromal and pro-tumorigenic inflammation was associated with a worse response. It appears to be a balance of these signatures that may inform CPI response.
Lastly, a combination of ICIs with multitargeted TKI’s (cabozantinib and sitravatinib) is also being explored. These too have demonstrated promising objective response rates.
His take-home message:
1. Combining drugs with single-agent activity is a pragmatic approach with a track record in oncology
2. Dissecting mechanisms of resistance still critical for major advances
3. We are on the verge of a new generation of PD-1/PD-L1-based combinations poised to enter our standard treatment algorithms.
Presented by: Matthew Galsky, MD, Professor of Medicine, Hematology and Medical Oncology, Professor of Urology at Mount Sinai Hospital, New York
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Assistant Professor of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, @tchandra_uromd on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.
References:
1. Wang L, Sfakianos JP, Beaumont KG, et al.. Myeloid Cell-associated Resistance to PD-1/PD-L1 Blockade in Urothelial Cancer Revealed Through Bulk and Single-cell RNA Sequencing. Clin Cancer Res. 2021 Apr 9. doi: 10.1158/1078-0432.CCR-20-4574. Epub ahead of print. PMID: 33837006