Chemotherapy: IO

Episode Notes

1. Biologic rationale for immunotherapy

1. Immune Checkpoints: immune checkpoints are ways in which normal/healthy cells (and tumors) avoid destruction by T-lymphocytes

1. PD-1 is a ligand which is responsible for preventing the immune system from attacking the body’s own tissues; PD-1 is expressed by T cells

2. PD-L1 is a receptor, expressed by tumors and healthy cells, which turns off the attack signal from T cells when bound to PD-1

1. Tumors have learned to upregulate expression of PD-L1 to evade the immune system

3. CTLA-4: receptor expressed in activated T lymphocytes which acts as an off-signal/down-regulator of T cell function

1. Cancers have learned to directly express CTLA-4 as well as to induce expression of regulatory T cells which heavily express CTLA-4, which helps avoid destruction by activated T cells

2. Immune checkpoint inhibition exploits the over-expression of immune checkpoints by tumor cells

1. Currently used:

1. Anti-PD-1

1. FDA Approved: Pembrolizumab, dostarlimab

2. Not yet FDA Approved: Cemiplimab, nivolumab, balstilimab

2. Anti-PD-L1

1. FDA approved: Durvalumab

2. Not yet FDA approved: Atezolizumab, avelumab

3. Anti-CTLA-4

1. Not yet FDA approved: Ipilimumab, falifrelimab

2. Predicting response

1. MSI: measured via tumor sequencing

2. MMRd: measured on IHC

3. TMB: measured via tumor sequencing

1. Foundation One CDX companion diagnostic

2. TMB ≥ 10 = “high TMB”

4. PD-L1: while used to predict response to immunotherapy, this has not been as successful at predicting response as MSI, MMR, TMB; most approvals for IO in gyn cancers are not based on PD-L1

1. Measured on IHC

2. Combined positivity score (CPS): PD-L1 expression in both tumor cells and immune cells (lymphocytes, macrophages) compared to the total number of viable tumor cells

1. CPS ≥ 1 = “positive”

3. Tumor Proportion Score (TPS): measures proportion of PD-L1 positive tumor cells compared to total number of tumor cells 

1. Not routinely used in gyn cancers

3. FDA approvals for immunotherapy in gyn cancers

1. Disease site agnostic

1. Based on MSI/MMRd status

1. Pembrolizumab: Based on results of KEYNOTE-158

1. Approved for patients with solid tumors which are MSIH/MMRd with disease progression following prior systemic therapy in any setting (if not a candidate for curative surgery or radiation)

2. Based on TMB-H status:

1. Pembrolizumab: based on the results of KEYNOTE-158

1. Approved for patients with solid tumors with unresectable or metastatic disease

2. Disease site specific

1. Endometrial Cancer

1. Pembrolizumab: Based on the results of NRG-GY018/KEYNOTE 868

1. Approved in combination with carbo/taxol, for the treatment of primary advanced or recurrent endometrial cancer

2. Approved for up to 2 years of use

3. See show notes from Uterine part 3 for trial inclusion criteria

2. Pembrolizumab, pMMR disease: Based on the results of KEYNOTE-775/Study 309

1. Approved, in combination with lenvatinib, in patients with pMMR disease, for recurrent endometrial cancer

2. See show notes from Uterine part 3 for trial inclusion criteria

3. Dostarlimab: Based on the results of ENGOT-EN-6-NSGO/GOG3031/RUBY trial

1. Approved in patients with advanced/recurrent endometrial cancer

2. Approved for up to 3 years of use

3. See show notes from Uterine part 3 for trial inclusion criteria

4. Durvalumab: for MMRd disease, Based on the results of the DUO-E/GOG-3041/ENGOT-EN10 study

1. Approved until disease progression/unacceptable toxicity

2. Approved, in combination with carbo/taxol for patients with advanced endometrial cancer

2. Cervical Cancer

1. Pembrolizumab: Based on the results of KEYNOTE-A18

1. Approved, in combination with chemoradiation, for patients with FIGO 2014 stage III-IVA disease

2. Pembrolizumab, for PD-L1 positive disease: based on the results of KEYNOTE-826

1. Approved for patients with PD-L1 positive, advanced disease (persistent/recurrent/metastatic), in combination with chemotherapy (+/- bevacizumab)

2. This is the only PD-L1 expression specific approval for pembrolizumab

3. Immune Related Adverse Events (IRAE)

1. IRAE are considered “off-target” effects of immune checkpoint inhibitors (remember that many healthy cells express PD-L1)

1. Can be a sign that the immune system is responding to the drug; sometimes patients with more IRAE have a stronger oncologic response.

2. Common: ≥ 70% of patients on Immune Checkpoint Inhibition (ICPi) experience some AE

1. 13% experience a grade 3+ event

3. Targets: any organ, any time!

1. Most commonly present in weeks to months after starting treatment, but can present even after stopping treatment (even years after)

1. Because of this, need to suspect IRAE in any patient currently or previously on ICPi 

2. Median time to presentation of IRAE with CTLA-4 inhibition tends to be shorter than with PD-1/PD-L1 inhibition.

2. Most common organ systems: skin, GI, endocrine, lung, liver, cardiovascular, CNS

3. Patients with earlier onset of AE are at higher risk of re-triggering the IRAE upon rechallenge

4. Management:

1. ASCO guidelines: management of IRAE treated with Immune Checkpoint Inhibitors

1. Detailed, system-specific, workup and management for IRAE

2. Because of complexity and breadth of types of presentations of IRAE, rely on this document to help guide management for specific toxicities

2. General principles (not applicable to all IRAE)

1. Evaluate the toxicity (H&P, labs, imaging) → consult ASCO guidelines → assign a grade→ treat

2. Steroids for majority of IRAE

1. If giving steroids for ≥ 28 days at high doses, consider PPI for stress ulcer prophylaxis, and consider prophylaxis for pneumocystis pneumonia (bactrim vs. alternate)

3. Management is based on grade

1. Grade 1: can continue the ICPi

1. symptomatic /supportive care

2. Grade 2: Temporarily stop the ICPi

1. Rechallenge with ICPi once symptoms resolve to ≤grade I severity

3. Grade 3-4: Stop the ICPi

1. High dose steroids with steroid taper for 4-6 weeks

2. If no improvement with high dose steroids in 48-72 hrs, may need to add monoclonal antibodies (eg: IVIG)

3. Grade 3: consider restarting ICPi once symptoms/labs revert to ≤ grade 1 severity

1. Consult specialists PRN

2. Consider restarting with shorter dosing intervals (q3w vs. q6w) in case symptoms recur

4. Grade 4: permanently discontinue ICPi

1. Urgent medical evaluation

2. Typically admit to hospital

3. High dose steroids as above

5. If previously on dual checkpoint blockade, consider restarting with monotherapy with the PD-1/PD-L1 agent

4. Dose adjustments? Generally not indicated for management of toxicities

5. When to rechallenge?

1. Symptoms and labs back to ≤ grade I levels

2. Consider timing with steroid taper

1. Steroid taper blunts the immune system; restarting the ICPi won’t be effective if patients are immunosuppressed with steroid taper

2. General principle (based on data from NSLC): consider restarting with total dose is ≤ 10mg prednisone (or equivalent) daily.

3. Exceptions to general principles

1. Endocrinopathies: cells producing hormones are often permanently damaged by the ICPi/no longer have the ability to make hormone and can’t recover

1. Management is based on repletion of hormone specific to the toxicity

2. Can continue the ICPi/do not need to discontinue, even for high-grade events (because stopping won’t fix or help the problem)

1. However, continuing the ICPi could still cause other IRAE; make sure to have a risk-benefit discussion with your patients

3. For thyroiditis, often follows the hyperthyroidism→burnout→hypothyroidism pathway as with other causes of thyroiditis. Treat symptomatically until hypothyroid, at which time you can replete.

4. Other forms of immunotherapy; none approved in gyn cancers to date

1. Therapeutic vaccines

2. Adoptive t cell therapy: tumor infiltrating lymphocyte therapy, chimeric antigen receptor (CAR) T cell therapy.

References

Check out the ASCO Guidelines !