Adjuvant oral agents in ER+ early breast cancer

 The OlympiA trial defined high-risk EBC as:

• HR-positive/HER2-negative: prior neoadjuvant CT and no pathologic complete response (pCR) plus a clinical and pathological stage plus estrogen receptor and nuclear grade (CPS + EG) score of 3 or more; prior adjuvant CT and at least 4 positive lymph nodes
• Triple-negative: prior neoadjuvant CT and no pCR; prior adjuvant CT and either node-positive or with a T2-T4 primary tumor at surgery

How to calculate CPS and EG score:

https://www3.mdanderson.org/app/medcalc/index.cfm?pagename=bcnt

• For patients with HR-positive/HER2-negative EBC who are eligible for both abemaciclib and olaparib, olaparib  is preferred because of proven OS benefit. This results in 1 year of adjuvant therapy with olaparib, which has a proven OS benefit, vs 2 (abemaciclib) or 3 (ribociclib) years of therapy with a CDK4/6 inhibitor and an unclear OS benefit at present. Do not give olaparib concurrently with a CDK4/6 inhibitor due to toxicity concerns.
• For patients with triple-negative EBC who are candidates for both olaparib and capecitabine and/or receiving the KEYNOTE-522 regimen of (neo)adjuvant pembrolizumab, we are typically selecting olaparib over capecitabine. Both drugs have demonstrated an OS benefit. For patients at very high risk of recurrence, healthcare professionals can consider sequencing both oral therapies—administering capecitabine for 6 to 8 cycles and then initiating olaparib; however, data supporting this strategy are lacking at this time. For both capecitabine and olaparib, we are administering these concurrently with pembrolizumab, for patients continuing immunotherapy in the adjuvant setting.

Reference: https://clinicaloptions.com/CE-CME/oncology/her2-negative-ebc-with-gbrca-pv/18910-34891/content

How do you counsel patients on the benefit of: 

1.  Adjuvant olaparib in BRCA mutated patients? HR for OS after 3 yr, 0.68, 90% versus 87% Olaparib versus placebo

2. Adjuvant abemaciclib? 5 yr IDFS HR 0.68, no OS benefit

3. Adjuvant  Ribociclib? Inclusion: In patients with node-negative disease, the risk of recurrence was defined as grade 2 plus evidence of high risk (Ki67 index > 20%; Oncotype DX Breast Recurrence Score > 26; or via genomic risk profiling). Other criteria for high-risk disease included node-positive disease or stage II or III disease.  3-year invasive disease–free survival rate was 90.7% with ribociclib vs 87.6% without it. OS data not mature. 25 % risk reduction in stage III, 30% risk reduction of IDFS in stage II.

4. Adjuvant Capecitabine in TNBC? OS improved by 5% at 5 years. 89% xeloda versus 83%

Factor XI

 April 2024

Factor XI deficiency

• Rare prevelance is 1/1 million Caucasian/ Ashkenzi Jews
• However among rare bleeding disorders, it tops the list
• Deficiency - two types- quantitative and qualitative
• Severe disease if homozygous or compound heterozygous
• Severe def if factor XI levels < 15 to 20 IU/dl
• Clinical manifestations- due to injury, increased bleeding with circumcision, tonsillectomy, increased menstrual and post partum bleeding
• If no personal hx of bleeding, that was the best predictor of low risk. Also if levels > 40 IU
• Older pt- factor XI remains the same. Can use anticoagulation for Afib if no bleeding hx or def is not severe. Using factor XI / VII a to counteract bleeding after surgery can lead to thrombosis in rare cases.
• May develop inhibitors to Factor XI but don't get spontaneous bleeding
• No standard prophylaxis even if levels < 1%
• High risk surgery e.g neurosurgery- tranexamic acid, FFP, FXI concentrate, off label factor 7a
• Gross hematuria in GU surgery contraindication to antifibrinolytic such as tranexamic acid
• Minor surgery : 3-5 days TXA or EACA 
• Major surgery: 7-10 days of TXA or EACA, FFP, Factor XI and off label factor 7a recombinant( mostly for those with factor XI inhibitors from prior FFP)
• Dose of FFP 20 ml /kg q 24
• Dose of Factor XI 10-20 IU/kg repeat q 48 hr
• Dose of Novo Seven- single dose 10-15 microgram /kg

Factor XI inhibitors for VTE prevention

• Three categories- Monoclonal Ab, small molecule oral agents, DNA antisense oligonucleotide
• While Factor XI inhibitors reduced risk of VTE esp post op, these drugs were not effective in secondary stroke reduction
• Inferior efficacy compared to DOAC in Afib and stroke reduction
• These drugs caused less  bleeding than DOAC

Interesting MCQ question for ASH: Name the gene variation associated with gestational thrombocytopenia?

Ans: PEAR1 ( plt endothelial aggregation receptor)

EGFR TKI -adjuvant and metastatic

 Ref: New treatment options for EGFR mutated lung cancer ASCO

Adjuvant

1. ADAURA: osimertinib versus Gefitinib 3 yr adjuvant after R0 resection for stage IB-IIIA

5 yr OS 90% versus 80% for gefitinib.  The benefit was more pronounced with stage II-IIIA NSCLC for DFS and OS benefit. 3 years of osimertinib doubles the chance of 5-year survival for patients with surgically resected EGFR-mutant NSCLC.

2. PACIFIC trial- chemo rad --> durva SOC; EGFR mutated pt did not benefit in subgroup analysis. Ongoing LAURA trial to see if consolidation osimertinib rather than durvalumab should be the new SOC for this subgroup. PFS was improved with osimertinib per press release.

3. FLAURA2 evaluated the addition of platinum-pemetrexed CT to osimertinib among patients with treatment-naïve advanced EGFR-mutated NSCLC.The median PFS was significantly improved with the addition of CT (25.5 months v 16.7 months, HR, 0.62 [95% CI, 0.49 to 0.79], P < .001), and ORR was also higher (83% v 76%).55 CNS PFS was improved in the combination arm

4. The phase III MARIPOSA trial compared amivantamab, an EGFR-MET bispecific antibody, plus lazertinib against osimertinib monotherapy, using investigator-assessed PFS as the primary end point. A third arm lazertinib monotherapy was included to assess the contribution of individual components. Amivantamab plus lazertinib reported a significantly longer PFS compared with osimertinib (23.7 months v 16.6 months, HR, 0.70 [95% CI, 0.58 to 0.85], P < .001) although ORR was similar (86% v 85%.

Additional ref: