What are your top takeaways in Thoracic Cancers from ASCO 2022?
1. Abst 8502 - Quality metrics and survival after lung cancer surgery: More efficient work-ups and consistently high quality resections will likely do more to improve lung cancer survival than any adjuvant or neo-adjuvant therapy we can come up with. This is low-hanging, low-cost fruit.
2. Abst 9007 - CLN-081 for EGFR exon 20 insertions: Efficacy that seems to be in the same range as amivantimab and mobocertinib, with potentially less toxicity.
3. One disappointment: The hype surrounding neoadjuvant therapy. Standard of care for people with clinical stage IB-II NSCLC is surgery, which has a greater impact on survival than any neoadjuvant or adjuvant therapy. Everyone is ignoring the 5-10% of people who end up not going to surgery on the neoadjuvant trials - they were obviously fit enough to enroll on a trial, so the reason they did not have surgery must have something to do with the treatment or the delay in surgery. Surgery is still the primary curative modality for people with early stage NSCLC and the ability to have surgery should not be jeopardized based on early DFS/EFS data. The paucity of discussion of the importance of overall survival is also disappointing.
1. KRYSTAL-1: This was a phase II trial of adagrasib in patients with advanced KRAS G12C NSCLC. In 112 patients who had prior immunotherapy and prior chemotherapy, the response rate was 43% with a median duration of response of 8.5 months. While sotorasib is an approved agent, adagrasib could be another option for this large subset of advanced NSCLC and some of the details, such as resistance and CNS efficacy, may be different.
2. Lung-MAP S1800A: This cohort of the NCI Lung-MAP study was a randomized phase II comparing pembrolizumab + ramucirumab versus chemotherapy in patients who had prior PD(L)1 therapy and prior chemotherapy. There was a survival benefit, with an OS HR of 0.69 and improvement in the median from 11.6 to 14.5 months favoring immunotherapy, though there was no significant difference in RR or PFS. One challenge in interpreting results is any retreatment effect or inclusion of any patients with an atypical treatment response but promising outcomes.
3. CRESTONE: We saw initial results of seribantumab (anti-HER3 IgG2) in patients with NRG1 fusion cancers. While this was in the Developmental Therapeutics track, 11 of the 12 patients had NSCLC. NRG1 fusions are rare and hard to detect - RNA based NGS is needed - but this shows they are clearly actionable. Seribantumab had a RR of 36% in NSCLC with DCR of 91% with most responses still ongoing and median DOR not yet reached.
1. Outcomes of anti–PD-(L)1 therapy with or without chemotherapy (chemo) for first-line (1L) treatment of advanced non–small cell lung cancer (NSCLC) with PD-L1 score ≥ 50%: FDA pooled analysis.
This validates the lack of OS benefit in giving PDL1 high patients combination therapy, and validates the use of pembro monotherapy as first line for PDL1 high patients. This is one of the primary goals of SWOG’s INSIGNA, though that trial has been accruing slowly.
2. Serplulimab, a novel anti-PD-1 antibody, plus chemotherapy versus chemotherapy alone as first-line treatment for extensive-stage small-cell lung cancer: An international randomized phase 3 study.
First positive trial of a PD1 antibody. We typically consider these more effective than PDL1, but have only had PDL1 antibodies approved in this population. The improvement in mOS was more than we have seen with the antibodies we use (including the data out of China presented by the same investigator with a different PDL1 at AACR 2022).
3. Activity of adagrasib (MRTX849) in patients with KRASG12C-mutated NSCLC and active, untreated CNS metastases in the KRYSTAL-1 trial.
Confirms the activity of these small molecules in the CNS.
Additional:
4. Phase (Ph) 1/2a study of CLN-081 in patients (pts) with NSCLC with EGFR exon 20 insertion mutations (Ins20).
Promising agent for Exon20, potentially with better tox profile than amivantimab and mobo.
1. Plenary TDXD presentation: Impactful not only for breast cancer, and not even just for all HER2+ cancers, but for our understanding of ADCs. ADCs may replace cytotoxic chemotherapy for many patients. I think of them as "slightly targeted chemotherapy" -- advances in efficacy of chemo are badly needed.
2. Amivantamab studies: New option for EGFR exon 20, pretreated classical EGFR and MET del 14
3. Adagrasib: Not only effective, but also brain penetrant and combinable with pembro
1. SKYSCRAPER-02: Press release ahead of the meeting indicated the study didn't meet its endpoint. Data presented showed survival curves essentially overlapping, not even a numerical trend to favor the investigational arm of tiragolumab added to chemoimmunotherapy as 1st line treatment for extensive stage SCLC.
2. Lung-MAP substudy (non-matched arm) randomized phase II comparing pembrolizumab+ramucirumab (PR) versus standard of care (SOC)MD choice in NSCLC previously treated with immunotherapy and progression after at least 84 days on immunotherapy regimen: This study met OS endpoint, with median OS of 14.5 (PR) vs 11.5 (SOC), HR 0.69, p=0.05. Subgroup analysis suggests that OS (as well as PFS) benefit is seen across all PD-L1 level but appears to be most pronounced in those with squamous histology, high TMB as well as those who had sequential chemotherapy followed by immunotherapy. This observation needs further validation in a larger study.
3. CLN-081 phase I study in NSCLC with EGFR exon 20 insertions: This oral irreversible EGFR TKI against EGFR exon 20 insertion mutations appear to have comparable efficacy in terms of response rates and PFS reported to date with what appears to be a better toxicity profile (lower rates of diarrhea, paronychia, severe skin rash) as well as hints of CNS activity. Phase II enrollment is planned.