immunotherapy for metastatic bladder cancer

4 months 3 weeks ago #61549 by Alan

DX 5/6/2008 TAG3 papillary tumor .5 CM in size. 2 TURBS followed by 6 instillations of BCG weekly with a second round of 6 after a 6 week wait.

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4 months 3 weeks ago - 4 months 3 weeks ago #61543 by joea73
Replied by joea73 on topic immunotherapy for metastatic bladder cancer

Immunotherapies which have been approved for solid tumors such as for bladder cancers are so called immune check point inhibitors.
Bladder cancers have been analyzed and shown to have many gene mutations - high tumor mutation burden (TMB).  Solid tumors with high send distress signal and our immune system responds to the distress signal and come near cancer cells to attack.  But, cancers have evolved over the time to escape from the attack from immune cells by waving "don't kill me because I am not dangerous" flags..  These flags are called PD-L1 or program death ligend-1.   Immune cells such as Killer T-cells (CD8+)  see "don't kill me" flags and go away without attacking the cancer cells.     PD-1 or program death - 1 protein on the surface of Killer T-cells plays a role to check if cells have PD-L1 proteins or not.    PD-1 is like brakes to stop T-cells to attack cancer cells.   One way o enable T-cells to attack cancer cells is by releasing its brakes.  The immunotherapy drug which releases the brake of T-cells is called PD-1 immune check point inhibitor.   The immunotherapy drug which removes "don't kill me flags" on cancer cells is called PD-L1 immune check point inhibitor.    Below are FDA approved immune check point inhibitors for bladder cancers that I am aware of.

PD-1 checkpoint inhibitor  :   Pembrolizumab (Keytruda),  Nivolumab (Opdivo) 
PD-L1 checkpoint inhibitor :  Atezolizumab (Tecentriq),  Avelumab (Bavencio),  Durvalumab (IMFINXI)

Clinical trials showed PD-1 checkpoint inhibitors and PD-L1 checkpoint inhibitors are about the same in its efficacy and side effects.
So, if one brand of  immune check point inhibitor stops working, oncologists usually do not offer another immunotherapy,

Erdafitinib (Balversa) (pill) is signal inhibitor for fiber blast  growth receptors (FGFR) which 30% of bladder cancers have mutations in FGFR genes.  When FGFR genes are mutated, it sends various signals to cell to divide.  Bladder cancer cells usually divide only once in 100-200 days.  When FGFR genes are mutated, it sends signals to cells to divide constantly.   Balversa inhibit those signals, thus preventing cancer cells to divide and grow constantly.

So, when an immune checkpoint inhibitor treatment does not work or stops working, another immune checkpoint inhibitor will not help.

FDA had approved two drugs  to treat such disease.  Both are targeted chemotherapy by using antibody as a vehicle to deliver very potent chemo agent to bladder cancers.  One is enfortumab vedotin-ejfv (PADCEV) and the other one is sactitzumab govitecan-hziy (Trodelvy). 

 PADCEV or some people call it EV are delivered to cells which express NECTIN-4 proteins on its membrane.  Bladder Cancers are known to express high numbers of NECTIN-4  protein on its cell membrane.     Once PADCEV links to Nectin-4 of a cancer cell, it releases potent chemo agent in side the cancer cell.  The chemo agent disrupts formation of microtubules just before the cell is divided into two daughter cells.  This leads to the cancer cells to die.  

TRODELVY is also classified as antibody-drug conjugate (ADC) to which PADCEV also belongs to.  TRODELVY uses antibody as vehicle to deliver different potent chemo agent to cancer cells.   TRODELVY targets cells with high expression of Trop-2 proteins which are often found in bladder cancer cells.  Once TRODELVY links to Trop2 protein of a cancer cell, it releases chemo agent SN-38 into the cell.  The chemo agent  SN-38 prevents inhibits unwinding of DNA in cell cycle.   As you know  DNA is that two RNAs which contain genes are twisted like spiral stair case.  For a cell to be divided,  DNA must be replicated.  The first step of DNA replication is to unwind DNA to make two RNAs. The chemo agent SN-38 of TRODELVY inhibits this unwinding DNA process, which leads to the cell death.

Since PADCEV had been approved first, it seems PADCEV is tried first.  If that does not work TRODELVY is tried.
Note that the clinical trial showed that TRODELVY works for patients who had PADCEV treatment as well as for patients who had not received PADCEV.

Immunotherapy + another agent  

Immunotherapy for bladder cancers work for about 25%.   To try to improve the efficacy of immunotherapy, there have been many studies and clinical trials, one of which is the combination of immunotherapy + another agent.    For example, the clinical trial  NCT03288545 is the combination of Keytruda + PADCEV has shown very good efficacy, which is much better than Keytruda alone or Padcev alone in its interim results.  They divided into 11 different cohorts (groups).  Most groups are those who had never received immunotherapy before.  But one group includes patients who had received immunotherapy - July 2022.   They stopped recruiting patients.  If the result were very good, the drug company usually seeks for accelerated approval from FDA.  I am not sure the timing may not suit you.  In this case, Padcev is likely the next treatment.

The following user(s) said Thank You: Alan

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4 months 4 weeks ago #61537 by Alan
Welcome ruralwmn,

We are sorry for the reasons to be here. The one drug that I have seen the most talked about the past year is Keytruda. I know it is an immunotherapy drug. Beyond the normal search engine finds I don't have any experience except that is does appear to be helping many patients.

DX 5/6/2008 TAG3 papillary tumor .5 CM in size. 2 TURBS followed by 6 instillations of BCG weekly with a second round of 6 after a 6 week wait.

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4 months 4 weeks ago #61536 by ruralwmn
I am wondering what immunotherapy drugs  some people have had with mets to lungs. I had my cystectomy in 2016 for a neo bladder.
Was clear for a year. It returned to my lung in one tumor. Had radiation and then chemo with Gem/Cis. Again clear for a year. Then returned to another are in lung. radiation again and had infusions of Tecentriq immunotherapy for 2 years. Was clear again. Came back in pelvic bone. Tried chemo Balversa (pill) for 6 months. Kept cancer stable but side effects were too much. Stopped Balversa and started 
back on Tecentriq.  On Tecentriq for 4 months and cancer has spread again. Wondering what else we can try.  Is there one of the immunotherapy drugs that works better? 
Really need some advice.

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