The Pointer Sisters and Shania Twain Strike Again!

We are working diligently to launch our ecosystem this year. Accordingly, I apologize for being a bit MIA.

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For many months I commented on every FDA approval in the hematology and oncology space using the patented Pointer Sisters ("I'm so excited") and Shania Twain ("That don't impress me much") rating system.

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Over the last month or so, while I have been largely quiet, there were several FDA approvals in oncology.

I didn't formally comment or rate them because they were exceedingly boring to me and really didn't get me out of bed.

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Now, with yesterday's FDA approval of padcev + keytruda for first-line treatment of patients with cisplatin-ineligible metastatic urothelial cancer, it's time for me to rise from my slumber and provide a perspective you can't really get anywhere else.

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But I will do one better than that. I will go over all the FDA approvals in oncology I intentionally slept on just for completeness' sake.

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2/9/23 - FDA grants regular approval to dostarlimab-gxly for mismatch repair deficient (dMMR) endometrial cancer:

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BORING!

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Dostarlimab-gxly already had accelerated approval in this setting. Indeed, it is in this exact setting that dostarlimab received it's VERY FIRST FDA approval. In fact, GSK was very smart in testing dostarlimab in endometrial cancer as it was THE FIRST PD-1 antibody approved in this setting; keytruda has since joined its ranks. With all of that said this approval gets 1 Shania Twain from me, not because it's not great, but just because accelerated approvals becoming regular approvals just doesn't do it for me. However, absolutely be on the lookout for dostarlimab and keytruda moving into first-line treatment of endometrial cancer in conjunction with chemotherapy as both drugs recently had positive data in this setting.

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3/3/23: FDA approval to extend abemaciclib use for adjuvant hormone-receptor positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence.

Initially, abemaciclib was only approved in node-positive patients with a Ki67 of 20% or more. This was always bullshit to me as it was basically an arbitrary measure used by Eli Lilly and company to find a way to get the drug approved.

Basically, they used regression analysis to stratify responders and non-responders in a way that allowed them to identify a subpopulation that potentially benefitted from abemaciclib to get it through the FDA. To this end, the updated FDA approval removes the Ki67 stipulation from abemaciclib use. This gets a neutral rating from me as abemaciclib's benefit is largely incremental in this setting and I would basically use it off-label irrespective of Ki67. This does make it easier from an insurance perspective. And what I do find interesting is that palbociclib failed in this setting, which lends further credence to the notion that CDK4/6 inhibitors (ribociclib included) are not all created equal. Ribociclib and abemaciclib showed an overall survival benefit in metastatic hormone-receptor positive/HER2-negative breast cancer, whereas palbociclib did not.

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3/16/23 - FDA approves dabrafenib/trametinib for pediatric patietns with BRAF V600E mutated low-grade glioma: These approvals make me mad. Indeed, the FDA is currently considering 2 drugs for Amyotrophic Lateral Sclerosis that DIDN'T even meet their primary endpoints in trial. Yet, here we have targeted therapies that we know are safe in adults and work extremely well in various circumstances that numerous children DID NOT receive because FDA hoops had to be jumped through. In fact, the FDA recently granted a tumor agnostic approval to dabrafenib/trametinib for BRAF V600E mutated tumors in adults, so what gives here? We absolutely need to change the way we regulate targeted therapies that have been proven safe, but that's a topic for a different day. Ultimately, this approval gets 1 POINTER SISTER from me because that's basically my floor for any drugs approved for children. If this was for adults it would get 2 SHANIA TWAINS as it just doesn't move the needle as we could often get these drugs off label and now they have a tumor agnostic approval anyways.

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3/22/23: The FDA granted accelerated approval to retifanlimab-dlwr for adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma:

BORING!

Keytruda, a PD-1 antibody JUST LIKE retifanlimab-dlwr, is ALREADY APPROVED in this setting so the addition of retifanlimab-dlwr DOES NOT MOVE THE NEEDLE AT ALL FOR PATIENTS. With that said this is Incyte's first foray into the world of FDA approved PD-1 antibodies which is good on them and sets them up for combination trials. It also helps alleviate some of the burn of having their retifanlimab-dlwr anal cancer trials fail. Regardless, I would be remiss if I didn't give this 1 SHANIA TWAIN. I would give it 2, but Incyte deserves credit for bringing a keytruda competitor to Merkel Cell cancer. Competition is always good.

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YESTERDAY: FDA approves padcev + keytruda for first-line treatment of patients with cisplatin-ineligible metastatic urothelial cancer.

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OK... let's add a little perspective here.

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Stage 4 urothelial cancer, including bladder cancer, urethral cancer, and upper tract urinary cancer (e.g renal pelvis, ureter, etc.) are generally incurable. A staple of the first-line treatment of such patients has been the use of cisplatin with gemcitabine. In fact, despite their rudimentary nature and toxicity profile, these chemotherapy drugs simply haven't been supplanted from their urothelial cancer throne despite many attempts to do so.

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The problem is that cisplatin is perhaps the most hated chemotherapy among oncologists. For me, it is probably number 1, but taxol (neuropathy) is a close second.

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The reason we loathe cisplatin is that it readily damages hearing and renal function, and there is very little one can do about it (sodium thiosulfate was recently approved to help prevent hearing loss). We aggressively hydrate patients when they receive cisplatin and often use MESNA, but even then the drug can leave patients with chronic renal failure and hearing loss. Not to mention the drug has a high propensity for causing nausea, but fortunately we are very good at protecting against this.

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Nonetheless, as metastatic urothelial cancer often affects older patients, many people with such malignancies cannot receive cisplatin due to preceding kidney dysfunction, hearing loss, or performance status concerns.

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I personally have had tremendous success substituting a different platinum drug, carboplatin, in place of cisplatin, although the conventional dogma used to be that carboplatin simply shouldn't be used in this setting (this has changed a bit as people are finally realizing something I was seeing in my patients long ago).

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Regardless, there is no question that treatments that don't utilize cisplatin and are effective are in dire need.

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Enter enfortumab vedotin-ejfv (Padcev) +keytruda.

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Padcev is a nectin-4 antibody drug conjugate that utilizes vedotin as the chemotherapy arm. Vedotin is a topoisomerase 1 inhibitor, similar to deruxtucan used in Enhertu, irinotecan, topotecan, etc. In fact, vedotin is the same chemotherapy arm employed in sacituzumab vedotin, brentuximab vedotin, and tisotumab vedotin, all of which are made by Seagen (more on this later).

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Keytruda, as everyone knows, is a PD-1 antibody and may very well be the most prescribed drug in all of oncology. It garnered 20.9 billion dollars in revenue for Merck last year.

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Ultimately, Padcev + keytruda, vai the EV-103/KEYNOTE-869 trial, was found to have an overall response rate of 68% in 121 patients, including 12% with a complete response. The median duration of response was 22 months.

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You can take it from me, as someone who treats a fair share of metastatic urothelial cancer, those are excellent numbers. Now, this comes as no surprise as this data was available many months ago and this FDA approval of Padcev + keytruda was a foregone conclusion. Regardless, this garners 1 POINTER SISTER from me.

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The approval of Padcev/keytruda is nice to have available for our patients with stage 4 urothelial cancer. There is no denying that. I'm just not fully convinced it's a major upgrade over current standards of care. Allow me to elaborate...

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Current standard of care for patients that CAN have cisplatin/gemcitabine front-line is:

1st-line: cisplatin/gemcitabine followed by avelumab maintenance

2nd-line: Padcev

3rd-line: Trodelvy

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To this end, even if we don't give patients cisplatin we were still giving them a PD-1 antibody (avelumab), like keytruda, and Padcev sequentially.

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It's certainly conceivable giving the a PD-1 antibody concurrent with Padcev is more effective than using a PD-1 antibody (avelumab) followed by Padcev, but I'm not fully convinced of that. Hence, the docking of 1 POINTER SISTER.

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But let's talk company implications for a minute...

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This approval is a coup for Seagen, even though it was a foregone conclusion. It firmly establishes them in a space one can argue they already dominated with Padcev and Trodelvy as two of the few viable options in this space.

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This approval is also big for Pfizer. In fact, I'm 100% certain this expected approval was factored into the 43 billion Pfizer paid for Seagen recently.

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This approval is big for keytruda. Keytruda has been punched in the face time and again in urothelial cancer as it failed to gain significant footing in this malignancy, in my opinion, until yesterday. In fact, until yesterday avelumab was THE PRIMARY PD-1 OR PD-L1 ANTIBODY used in stage 4 urothelial cancer with atezolizumab and durvalumab suffering major setbacks and being pulled off the market, and avelumab being approved in the maintenance setting post cisplatin/gemcitabine. Merck was desperate to infiltrate this space more profoundly, and now they get to piggyback on Padcev to do it.

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There are no surprises here. It's what companies do. Indeed, there is no semblance of intellect required to devise a Padcev/keytruda trial. All people are doing is mixing approved drug A with the drug they wish to get in the space and coming up with a contrived justification for it. I could show you hundreds of trials being done along these lines. There is nothing special about it, but in this case it worked for Merck and will help them garner market share in a forum they had none.

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And with that, we're all caught up on FDA approvals in the oncology forum. I will be back for more whenever the FDA comes calling.

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Status is online

Basem Goueli MD/PhD/MBA

CEO and Founder of CancerLight, CEO and Founder of CancerClarity, Medical Director for Xbiotech, Pharmaceutical Consultant, Full-time Hematologist/Medical Oncologist

Published ? 1m

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We are working diligently to launch our ecosystem this year. Accordingly, I apologize for being a bit MIA.

For many months I commented on every FDA approval in the hematology and oncology space using the patented Pointer Sisters ("I'm so excited") and Shania Twain ("That don't impress me much") rating system.

Over the last month or so, while I have been largely quiet, there were several FDA approvals in oncology.

I didn't formally comment or rate them because they were exceedingly boring to me and really didn't get me out of bed.

Now, with yesterday's FDA approval of enfortumab + keytruda for first-line treatment of patients with cisplatin-ineligible metastatic urothelial cancer, it's time for me to rise from my slumber and provide a perspective you can't really get anywhere else.

But I will do one better than that. I will go over all the FDA approvals in oncology I intentionally slept on just for completeness' sake.

If you want to read something NOBODY ELSE CAN GIVE YOU click on the article below.

I am not playing the same game they are, and I'm including the Dana Farbers, Sloan Ketterings, etc.

Indeed, by now everyone should know I don't believe that where you are is necessarily a reflection of your expertise, talent, etc.

In fact, the word "expert" has been so overused of late that it has essentially no meaning in my world.

One of the best examples I can give you is that we have trainees (fellows in oncology) that are literally being lauded as breast cancer "experts" when I have numerous colleagues who have literally seen thousands more breast cancer patients than they have.

It just doesn't mean a lot to me.

Show me what you know is truly unique, regardless of where you're employed, and then we can talk.

Case in point...