Non small cell lung ca without oncogenic mutations

 

Single agent immunotherapy versus chemo

1. Single agent Pembro for PD1 > 50%- Key note 024. In the absence of disease progression, pembro was given for 2 yr. OS a little over 2 yr in pembro arm compared to 1 yr in control arm. Better PFS and ORR. Less grade 3 or higher toxicity 25% versus 50%. 

5 yr OS- 32% versus 16%

2. Pembro versus chemo  PDL1 greater than 1%- Keynote 042:  There was an OS benefit in all groups but the vast majority had TPS > 20% and almost half had TPS > 50%.

20 m, 16 m and 17 m versus 13 months in TPS 50%, 20% and > 1% respectively

3. Where does cemiplimab come in? And why is it different from Pembro?

In patients with stage III disease with > 50% PDL1 who are not candidates for curative rx or chemoradiation, cemiplimab has an official indication. It can also be continued at progression, if chemo can be added on. But PDL1 had to be 50% or higher. EMPOWER 1 trial.

4.  Atezolizumab is also approved in this space for PDL1> 1%

Immunotherapy with chemo

1. Keynote 189 Pembro with chemo irrespective of PDL1 status improves OS in all comers.

Pembro was for 2 yr. Pem continued until progression or toxicity.

If patients could complete the 2 yr pembro, the ORR 86% and OS was 71%.

HR for OS 0.6 and for PFS 0.5 over 5 yr

5 yr OS 20% pembro +chemo versus 11%

Note: Cemiplimab plus chemo also approved in this space with similar OS HR, but PDL1 has be to be > 1% whereas pembro can be used even in PDL1 < 1% in combination with chemo.

2. Atezo combinations approved ( can use if EGFR/ALK mutated)- OS HR 0.8 for both

IMPOWER 150- ABCP- Atezo+Bev+ Carbo+Taxol

IM POWER 130- Atezo+ Carbo+ Abraxane 

3. Squamous cell-Keynote 047- pembro with carbo and nab paclitaxel approved for all comers, but OS benefit decreased with follow up in PDL 1 neg.

HR 0.71 all comers, OS 1.5 yr versus 1 yr

Immunotherapy doublet  

Ipi Nivo FDA approved irrespective of PDL1- Checkmate 227

- OS HR 0.6 if PDL1 neg, 0.8 if PDL1> 1

- Six yr OS 16% ( PDL1  neg) 22% PDL 1  positive

Immunotherapy doublet + chemo

1. 9LA regimen- Ipi Nivo ( 1+3) with chemo 2 cycles- benefit if PDL1 < 1 % or squamous. OS 17 months. HR 0.7

2. Durva+ Tremelimumab+ chemo-POSEIDON trial- approved.

Factors favoring monotherapy versus combination

• single agent IO if PDL1> 50%= men, smokers, TP53 mutated, KARS G12 C TP53 mutated. Age over 75 yr.
• favoring combination chemo with IO= females, never smokers, STK11, all other KRAS

Interesting points about mutations:

• KRAS G12 C with TP53 co-mutation : KRAS G12C/TP53 comutated patients are elite-controllers, deriving the highest ORR and longest duration of response and PFS, associated with an inflamed TME and upregulation of interferon gamma-related proinflammatory pathways.
• The benefit of IO was lost in STK deficient tumors. STK is a phenotype rather than mutation.
• CheckMate 227, 9LA, and POSEIDON suggest improved OS with dual checkpoint blockade in KRAS negative, STK11-, and/or KEAP1-mutated patients.

Second line

Docetaxel+/= ramucirumab

currently no established benefit of a continued ICI administration combined with anti–vascular endothelial growth factor or any other targeted strategy, respectively, after failure of up-front ICI-based treatments

My approach:

At the time of initial visit, most patients do not have NGS testing completed. If symptomatic and require immediate rx, the options for rx include Ipi+ nivo+chemo doublet in squamous cell carcinoma or carbo-Pem-Pembro in adenocarcinoma pending NGS results.

Reference: https://ascopubs.org/doi/full/10.1200/EDBK_432524