Thank you ydgcauThe previous reply came without editing all the...

Thank you ydgcau

The previous reply came without editing all the spaces and is unreadable.

When looking for comparable solid tumor drugs approved based on single-arm studies in recent years, ORR and mDoR is based on a larger number of patients (N=65-120) than 40 patients (TACTI002+003) of whom 8-11 gets ORR. Based only on 8-11 patients I (or FDA) would need to know more about patient characteristics than their greatest tumor diameter change between the baseline and one of the follow-ups. To what extent of tumors and metastasis these ORR patients had, especially what is DoR and could it be given in addition to the existing therapy options without loss of efficacy or should it perform better alone against the existing options. MoA, toxicities, prior approvals and price/availability of the treatment are important. A possibility of a marginally effective “additional-drug” with huge costs doesn’t warm-up insurance providers even though the FDA would approve it.

It has to be taken into account that the only option for PD-L1 neg is chemotherapy which has short term response (4-5m mDoR in KN-048 & KN-040) and more toxicities compared to efti+aPD-1 which has hopefully long DoR as is shown in TACTI-002 data. Based on all the data to date, I would find it suspicious that efti+aPD-1 would not have a good increase in efficacy against pembro alone in the PD-L1 positive group, but somehow have a good efficacy in the PD-L1 negative group versus pembro alone. And to keep in mind, there is a lot of data that the corporation can give to the FDA to support the case that is not published in press releases or subsequent publications. For a simple example, it takes more efficacy to have a CR on a patient with a big primary tumor and multiple metastasis than on a patient with no primary tumor and 2cm asymptomatic metastasis found on a follow-up scan.One example of that FDA thinks about the response beside the dummy-categories of the greatest change between the baseline and one follow-up time point (PD-SD-PR-CR) is that Imugene got FTD after 1 patient (CR for 1 year) in cholangiocarcinoma. On the other hand if somebody comes with “a miracle”, say cures end-stage Alzheimer to functioning healthy elderly, then under a handful of them would be enough for AA. In the cancer setting, a very high evidence of action is the MSI-high rectal carcinoma neoadjuvant patients treated with aPD-1 (12/12 pathological CRs at the time of operation) compared to a quite toxic standard of care which has reasonable efficacy, too.

So, if I would act as a gatekeeper for the AA, PD-L1 neg single-arm would be judged by more on the qualitative aspects of the responder patients than by the actual number are they 8-11 per 30-40 or so. Also would put scrutiny on DoR that hopefully matures slowly. The PD-L1 pos group due to randomization and the almost perfect counterfactual (though in clinic chemo+pembro is likely a choice for many) would be judged more on the basis of ORR and mPFS. One reason for positivity regarding upcoming HNSCC 1L data is that PD-L1 neg group has a lot higher ORR (7/26) than the TACTI-002 2L data in which there was 1/8 CR in PD-L1 neg group and 0/5 ORR in PD-L1 non-evaluable group (likely some PD-L1 neg) and therefore the ORR was more or less 1/9-12. In most aPD-1 indications, there is better 1L than 2L+ results as chemo or other currently available drugs kill ‘easier’ cells or one-type of cells, tumor become more heterogeneous and tumor mass is on average larger in 2L than in 1L setting (larger tumors other things in constant have lesser ORR for aPD-1 in melanoma, NSCLC).

I've knowledge gaps in oncology and especially anything to preclinical related, but appraising the clinical data and possible source of biases has been my main focus in research.

My previous notes on the single-arm P2 solid tumor studies that resulted in AAs during last few years.
1. Retifanilimab (aPD-1) for Merkel cell cancer. P2 single-arm, N=65. ORR 52%: CR 18%, PR 34%, DoR ranged 1-25m. 10.1007/s40265-023-01884-7 No P3 yet.
2. Sotorasib (KRAS-inhibitor) for KRAS G12C mutated NSCLC. P2 single-arm, N=124. ORR 41%, mDoR 10m and PFS of 6.3m. PMC9012672 Subsequent P3, N=350, in 2-3L, 1:1 sotorasib vs docetaxel ORR 28% vs 13%, mDoR 8.6m vs 6.8m. 13% of all patients in docetaxel-arm dropped out before first treatment, see you randomized data. 10.1016/S0140-6736(23)00221-0
3. Adagarasib (KRAS-inhibitor) for KRAS G12C mutated NSCLC. P2 single-arm, N=112. ORR 43%, mDoR 8.5m and a PFS of 6.5m NEJMoa2204619. Subsequent P3, N=450, 1:1 adagarasib vs docetaxel in 2L. ORR 32% vs 9%, mDoR 8.3m vs 5.3m. Gr3 AE 47% vs 46%. BMS 6/1/2024
4. Mirvetuximab soravtansine (ADC) for ovarian cancer with FRa+ and plat-resistant, 50% was 4L+. P2 single-arm, N=100. ORR 32%: CR 5%, PR 28%, with mDoR 6.9m. Subsequent P3, N=450, 1:1 mirvetuximab against chemo in 2-4L patients. ORR 42% vs 16%, mDoR 6.8m vs 4.5m, mOS 16.5m vs 12.8m. NEJMoa2309169
5. Futibatinib (FGFR kinase inhibitor) for cholangiocarcinoma. P2 single-arm, N=104. ORR 42%: CR 1%, PR 41%, mDoR 9.7m. NEJMoa2206834. No P3 yet.
6. Mobocertinib (EGFR kinase inhibitor) for EGFR Exon 20 NSCLC. P2 single-arm, N=114, 2-3L. ORR 28%, mDoR 17.5m. 10.1016/j.jtho.2021.01.283 Subsequent P3 (N=350, 1:1) was negative in 1L setting against monocertinib vs pemetrexed+platin-chemo. In P3 ORR 32% vs 30%, mDoR 12m vs 8m, mPFS 9.6m vs 9.6m. 10.1016/j.annonc.2023.10.586
7. Sacituzumab Govitecan (ADC) for 3L metastatic urothelial cancer after platinum chemo+aPD-1. P2 single-arm, N=114. ORR 27%: CR 5%, PR 22%, mDoR 7.2m, mOS 11m. Subsequent P3 confirmatory trial did not show benefit in OS, PFS, ORR. N=700, 1:1 open label against chemo in the same 3L mUC setting. Gilead 5/30/2024