I lined G1 Therapeutics (NASDAQ:GTHX) in November, after they had been speaking about when to topline their colorectal most cancers trial. This was PRESERVE 1, the part 3 metastatic colorectal most cancers (mCRC) trial of trilaciclib, which was totally enrolled in June and was slated to topline in 1H2023.
I referred to as this a high-risk/reward binary occasion; the danger half comes from the dearth of part 2 information, and the reward half comes from the truth that mCRC is a 5x bigger market than trilaciclib’s presently authorized indication. There’s additionally the truth that trilaciclib works in a tumor-agnostic method, and in non-mCRPC settings, it has proven us wonderful information. All these items made me have a look at GTHX with some hope.
I used to be, due to this fact, shocked to note at the moment that the inventory is down 60% from its November costs, and the reason being that the pivotal PRESERVE 1 trial was halted.
PRESERVE 1 was a randomized, placebo-controlled pivotal Part 3 trial of trilaciclib in 326 sufferers with metastatic CRC receiving first line trilaciclib or placebo administered previous to FOLFOXIRI (a mixture of fluorouracil (5-FU), folinic acid, oxaliplatin and irinotecan) and bevacizumab. Whereas no part 2 information was out there for this indication, information introduced from a TNBC trial confirmed that trilaciclib might have a job in T-cell infiltration unbiased of tumor sort. So there was some hope of success in mCRC.
Nevertheless, halting the trial on poor efficacy modified all that. Information confirmed that the placebo arm of the research, PRESERVE 1, outperformed “the trilaciclib arm for anti-tumor efficacy, together with total response price (ORR) and preliminary measures of survival.” Because it says on on the registry:
Terminated (Regardless of reaching co-primary endpoints & different secondary measures of myeloprotection & tolerability, early anti-tumor efficacy information favor sufferers receiving placebo. Given the low probability of reaching PFS & OS endpoints, G1 determined to discontinue)
Thus, this was an fascinating state of affairs the place the trial met the co-primary endpoints with statistical significance, however was then deserted as a result of it didn’t attain sure survival advantages and different medical measures. Trilaciclib is primarily a myelopreservation agent, and on this entrance this was a profitable trial.
Of their March earnings name, the corporate supplied the next perception into the information we noticed with PRESERVE 1:
This hostile impact on anti-tumor efficacy seems to be restricted to this chemotherapy routine utilized in colorectal most cancers as different medical trials of trilaciclib together with completely different chemotherapies in sufferers with extensive-stage small cell lung most cancers and triple-negative breast most cancers didn’t display this hostile anti-tumor efficacy sign. In truth, within the Part II triple-negative breast most cancers research, we noticed the other – a statistically important enchancment in total survival in sufferers receiving trilaciclib in comparison with placebo.
We’re conducting quite a lot of analyses to know the outcomes. For instance, we’re trying into the likelihood that trilaciclib might have had an unanticipated unfavorable interplay with 5-FU which might not have been recognized as a danger in any of the preclinical assessments we carried out. We glance to speak the outcomes of those and different analyses over the approaching few months.
Two months later, of their Might earnings name, upon being requested for such updates, the corporate didn’t provide a lot readability:
… we are literally doing quite a few investigations presently. And so when we’ve these information we are going to clearly launch them.
The analyst requested an fascinating query about information generated by sure trials that apparently confirmed an antagonistic impact between CDK4/6 inhibitors (like trilaciclib) and the 5-FU routine given within the mCRC trial. The analyst requested whether or not GTHX noticed something related of their preclinical fashions. The corporate stated the next:
Sure. So, particularly for preclinical work, I imply we had carried out with 5-FU together, really it was a checkpoint inhibitor was trila, which confirmed an enchancment in efficacy. And we in fact, had numerous information with just a few displaying that myeloprotection advantages. So, once more, there was no – there was definitely no information pre-clinically to recommend that we might see what we noticed in colorectal. And we additionally did that work with different chemo therapies as effectively. We’re undoubtedly increasing our work with completely different chemotherapies now given this information to higher perceive it.
Now, there’s really analysis that reveals the antagonism between CDK4/6 and chemo, in addition to the synergy between them. The result’s, thus, inconslusive. As some analysis says:
Because of their affect on the cell cycle, CDK4/6 inhibitors (CDK4/6i) have been hypothesized to antagonize the anti-tumor results of cytotoxic chemotherapy in tumors which are CDK4/6 dependent. Nevertheless, there are a number of preclinical research that illustrate potent cooperation between CDK4/6i and chemotherapy.
Certainly, three authorized CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib have been proven to “improve, reasonably than antagonize, chemotherapy cytotoxicity when mixed with camptothecin, carboplatin, cisplatin, docetaxel, doxorubicin, 5FU, gemcitabine, irinotecan, paclitaxel, and temozolomide.” As we are able to see, this record additionally contains 5-FU, the identical routine concerned in PRESERVE 1.
Thus, there appears to be hope that no matter it was, it was not some sad interplay between chemotherapies typically and trilaciclib, so different trials, notably the one in TNBC, won’t endure an analogous destiny. As the corporate identified:
Lastly, our Part III trial in triple-negative breast most cancers relies on the foundational information from our Part II trial that confirmed a statistically important survival benefit for sufferers enrolled in each trilaciclib arms in comparison with placebo.
Thus, the mCRC factor could also be an outlier – too unhealthy they didn’t do a part 2 on this indication.
Anyway, the corporate has shut down that trial, and lower some 30% of its workforce to protect money. Its ES-SCLC income from Cosela has improved, as I mentioned even in my final article. What we are able to sit up for now are bettering revenues from this indication, and progress with the TNBC indication.
GTHX has a market cap of $143mn, and a money stability of $116mn. Income was $12.9mn. Price of products bought was $1.5mn. R&D was $15.5mn, whereas G&A was $21.8mn. Thus, the corporate’s money place is sort of precarious, and they’re making some efforts, for instance by “monetizing the longer term royalties and milestones from Simcere which brings us $30 million as of the present quarter and as much as $48 million in whole.”
GTHX has by no means carried out too effectively with ES-SCLC, one purpose for which is the small market dimension, one other is the preliminary hiccup with its business accomplice, and the third is, like we noticed earlier, the small firm’s lack of enough networking capabilities to enroll giant distributor companions. The money place is poor, and the failure within the one indication has damage them. No matter might have been the explanation for the failure, administration could also be blamed, maybe rightly so, for his or her failure to do a part 2, or an early basket trial, in mCRC, to be able to keep away from simply this type of costly failure.
GTHX inventory is buying and selling very low proper now, and there are causes some would possibly think about it a purchase. There may be definitely room for enchancment right here. Nevertheless, I’m going to keep away from, given my earlier optimistic expertise with the inventory. I don’t need to push my luck.