A novel strategy involves combining antibody-drug conjugates (ADCs) with PARP inhibitors. This approach could potentially overcome the need for a germline BRCA mutation, significantly broadening the patient population that could benefit from PARP inhibitor therapy in triple-negative breast cancer.

After a triple-negative breast cancer patient progresses on a first-line TROP2 antibody-drug conjugate (ADC), experts advise against immediately sequencing another ADC. Due to suspected cross-resistance, the recommended strategy is to return to traditional chemotherapy agents like taxanes or carboplatin, which remain effective options, before considering another ADC in later lines.

Despite initial preclinical concerns that HIF-2 inhibition might dampen immune response, the success of the Pembro+Belzutifan combination is likely due to the simple additive effect of two active drugs. Newer data refutes the immune-dampening theory, showing no negative impact on the tumor microenvironment and possibly even a reduction in immunosuppressive cells.

A common clinical observation is that patients who develop significant immune-related toxicities, like colitis or pneumonitis, are frequently the same ones who experience the most profound and durable responses to checkpoint inhibitor therapy.

In the Keynote 522 trial for early-stage TNBC, adding pembrolizumab to chemotherapy resulted in only a modest improvement in pathological complete response (pCR). Surprisingly, this small initial gain translated into much more robust and significant long-term improvements in event-free and overall survival.

The KEYNOTE-756 and Checkmate 7FL trials found high pathological complete response (pCR) rates with neoadjuvant immunotherapy in ER-low (1-10%) breast cancers. This suggests this unique subgroup, often excluded from triple-negative trials but behaving similarly, may benefit significantly from immunotherapy, though it is not yet standard of care.

Contrary to the assumption that two drugs are always more toxic than one, the Lenvatinib-Belzutifan combination in the LightSpark-011 trial presented a different, but not quantifiably worse, toxicity profile compared to cabozantinib monotherapy, challenging conventional thinking on combination therapy side effects.

Data shows that patients who permanently stopped ipilimumab due to immune-related side effects still had exceptionally good outcomes. This gives clinicians confidence to manage toxicity by discontinuing the CTLA-4 inhibitor portion of the regimen while continuing nivolumab, without fearing a loss of efficacy.

Contrary to the assumption that combinations are more toxic, Lenvatinib/Belzutifan showed a different side effect profile, not a worse one, compared to single-agent Cabozantinib. The combo caused more anemia while Cabozantinib caused more diarrhea and skin toxicity, but treatment discontinuation rates were identical at 11% for both arms.